Thin film with non-self-aggregating uniform heterogeneity and drug delivery systems made therefrom

ABSTRACT

The invention relates to film products containing desired levels of active components and methods of their preparation. Desirably, the films disintegrate in water and may be formed by a controlled drying process, or other process that maintains the required uniformity of the film. Desirably, the films may be exposed to temperatures above that at which the active components typically degrade without concern for loss of the desired activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. application Ser. No.10/768,809, filed Jan. 30, 2004, which claims benefit to U.S.Provisional Application No. 60/443,741 filed Jan. 30, 2003, and which isa continuation-in-part of PCT/US02/32575 filed Oct. 11, 2002, whichclaims priority to U.S. application Ser. No. 10/074,272, filed Feb. 14,2002 which claims priority to U.S. Provisional Application No.60/328,868, filed Oct. 12, 2001 and U.S. Provisional Application No.60/386,937, filed Jun. 7, 2002; U.S. application Ser. No. 10/768,809 isalso a continuation-in-part of PCT/US02/32594, filed Oct. 11, 2002,which claims priority to U.S. Provisional Application No. 60/414,276,filed Sep. 27, 2002, U.S. application Ser. No. 10/074,272, filed Feb.14, 2002, which claims priority to U.S. Provisional Application No.60/328,868, filed Oct. 12, 2001 and U.S. Provisional Application No.60/386,937, filed Jun. 7, 2002; and U.S. application Ser. No. 10/768,809is also a continuation-in-part of PCT/US02/32542, filed Oct. 11, 2002,which claims priority to U.S. Provisional Application No. 60/371,940,filed Apr. 11, 2002, U.S. application Ser. No. 10/074,272, filed Feb.14, 2002, which claims priority to U.S. Provisional Application No.60/328,868, filed Oct. 12, 2001 and U.S. Provisional Application No.60/386,937, filed Jun. 7, 2002, the contents all of which areincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to rapidly dissolving films and methods of theirpreparation. The films contain an active ingredient that is evenlydistributed throughout the film. The even or uniform distribution isachieved by controlling one or more parameters, and particularly theelimination of air pockets prior to and during film formation and theuse of a drying process that reduces aggregation or conglomeration ofthe components in the film as it forms into a solid structure. Thedrying process further permits exposure of the film to temperaturesabove that at which the active ingredient typically would degradewithout loss of a desired level of activity.

BACKGROUND OF THE RELATED TECHNOLOGY

Active ingredients, such as drugs or pharmaceuticals, may be prepared ina tablet form to allow for accurate and consistent dosing. However, thisform of preparing and dispensing medications has many disadvantagesincluding that a large proportion of adjuvants that must be added toobtain a size able to be handled, that a larger medication form requiresadditional storage space, and that dispensing includes counting thetablets which has a tendency for inaccuracy. In addition, many persons,estimated to be as much as 28% of the population, have difficultyswallowing tablets. While tablets may be broken into smaller pieces oreven crushed as a means of overcoming swallowing difficulties, this isnot a suitable solution for many tablet or pill forms. For example,crushing or destroying the tablet or pill form to facilitate ingestion,alone or in admixture with food, may also destroy the controlled releaseproperties.

As an alternative to tablets and pills, films may be used to carryactive ingredients such as drugs, pharmaceuticals, and the like.However, historically films and the process of making drug deliverysystems therefrom have suffered from a number of unfavorablecharacteristics that have not allowed them to be used in practice.

Films that incorporate a pharmaceutically active ingredient aredisclosed in expired U.S. Pat. No. 4,136,145 to Fuchs, et al. (“Fuchs”).These films may be formed into a sheet, dried and then cut intoindividual doses. The Fuchs disclosure alleges the fabrication of auniform film, which includes the combination of water-soluble polymers,surfactants, flavors, sweeteners, plasticizers and drugs. Theseallegedly flexible films are disclosed as being useful for oral, topicalor enteral use. Examples of specific uses disclosed by Fuchs includeapplication of the films to mucosal membrane areas of the body,including the mouth, rectal, vaginal, nasal and ear areas.

Examination of films made in accordance with the process disclosed inFuchs, however, reveals that such films suffer from the aggregation orconglomeration of particles, i.e., self-aggregation, making theminherently non-uniform. This result can be attributed to Fuchs' processparameters, which although not disclosed likely include the use ofrelatively long drying times, thereby facilitating intermolecularattractive forces, convection forces, air flow and the like to form suchagglomeration.

The formation of agglomerates randomly distributes the film componentsand any active present as well. When large dosages are involved, a smallchange in the dimensions of the film would lead to a large difference inthe amount of active per film. If such films were to include low dosagesof active, it is possible that portions of the film may be substantiallydevoid of any active. Since sheets of film are usually cut into unitdoses, certain doses may therefore be devoid of or contain aninsufficient amount of active for the recommended treatment. Failure toachieve a high degree of accuracy with respect to the amount of activeingredient in the cut film can be harmful to the patient. For thisreason, dosage forms formed by processes such as Fuchs, would not likelymeet the stringent standards of governmental or regulatory agencies,such as the U.S. Federal Drug Administration (“FDA”), relating to thevariation of active in dosage forms. Currently, as required by variousworld regulatory authorities, dosage forms may not vary more than 10% inthe amount of active present. When applied to dosage units based onfilms, this virtually mandates that uniformity in the film be present.

The problems of self-aggregation leading to non-uniformity of a filmwere addressed in U.S. Pat. No. 4,849,246 to Schmidt (“Schmidt”).Schmidt specifically pointed out that the methods disclosed by Fuchs didnot provide a uniform film and recognized that that the creation of anon-uniform film necessarily prevents accurate dosing, which asdiscussed above is especially important in the pharmaceutical area.Schmidt abandoned the idea that a mono-layer film, such as described byFuchs, may provide an accurate dosage form and instead attempted tosolve this problem by forming a multi-layered film. Moreover, hisprocess is a multi-step process that adds expense and complexity and isnot practical for commercial use.

Other U.S. patents directly addressed the problems of particleself-aggregation and non-uniformity inherent in conventional filmforming techniques. In one attempt to overcome non-uniformity, U.S. Pat.No. 5,629,003 to Horstmann et al. and U.S. Pat. No. 5,948,430 to Zerbeet al. incorporated additional ingredients, i.e. gel formers andpolyhydric alcohols respectively, to increase the viscosity of the filmprior to drying in an effort to reduce aggregation of the components inthe film. These methods have the disadvantage of requiring additionalcomponents, which translates to additional cost and manufacturing steps.Furthermore, both methods employ the use the conventional time-consumingdrying methods such as a high-temperature air-bath using a drying oven,drying tunnel, vacuum drier, or other such drying equipment. The longlength of drying time aids in promoting the aggregation of the activeand other adjuvant, notwithstanding the use of viscosity modifiers. Suchprocesses also run the risk of exposing the active, i.e., a drug, orvitamin C, or other components to prolonged exposure to moisture andelevated temperatures, which may render it ineffective or even harmful.

In addition to the concerns associated with degradation of an activeduring extended exposure to moisture, the conventional drying methodsthemselves are unable to provide uniform films. The length of heatexposure during conventional processing, often referred to as the “heathistory”, and the manner in which such heat is applied, have a directeffect on the formation and morphology of the resultant film product.Uniformity is particularly difficult to achieve via conventional dryingmethods where a relatively thicker film, which is well-suited for theincorporation of a drug active, is desired. Thicker uniform films aremore difficult to achieve because the surfaces of the film and the innerportions of the film do not experience the same external conditionssimultaneously during drying. Thus, observation of relatively thickfilms made from such conventional processing shows a non-uniformstructure caused by convection and intermolecular forces and requiresgreater than 10% moisture to remain flexible. The amount of freemoisture can often interfere over time with the drug leading to potencyissues and therefore inconsistency in the final product.

Conventional drying methods generally include the use of forced hot airusing a drying oven, drying tunnel, and the like. The difficulty inachieving a uniform film is directly related to the rheologicalproperties and the process of water evaporation in the film-formingcomposition. When the surface of an aqueous polymer solution iscontacted with a high temperature air current, such as a film-formingcomposition passing through a hot air oven, the surface water isimmediately evaporated forming a polymer film or skin on the surface.This seals the remainder of the aqueous film-forming composition beneaththe surface, forming a barrier through which the remaining water mustforce itself as it is evaporated in order to achieve a dried film. Asthe temperature outside the film continues to increase, water vaporpressure builds up under the surface of the film, stretching the surfaceof the film, and ultimately ripping the film surface open allowing thewater vapor to escape. As soon as the water vapor has escaped, thepolymer film surface reforms, and this process is repeated, until thefilm is completely dried. The result of the repeated destruction andreformation of the film surface is observed as a “ripple effect” whichproduces an uneven, and therefore non-uniform film. Frequently,depending on the polymer, a surface will seal so tightly that theremaining water is difficult to remove, leading to very long dryingtimes, higher temperatures, and higher energy costs.

Other factors, such as mixing techniques, also play a role in themanufacture of a pharmaceutical film suitable for commercialization andregulatory approval. Air can be trapped in the composition during themixing process or later during the film making process, which can leavevoids in the film product as the moisture evaporates during the dryingstage. The film frequently collapse around the voids resulting in anuneven film surface and therefore, non-uniformity of the final filmproduct. Uniformity is still affected even if the voids in the filmcaused by air bubbles do not collapse. This situation also provides anon-uniform film in that the spaces, which are not uniformlydistributed, are occupying area that would otherwise be occupied by thefilm composition. None of the above-mentioned patents either addressesor proposes a solution to the problems caused by air that has beenintroduced to the film.

Therefore, there is a need for methods and compositions for filmproducts, which use a minimal number of materials or components, andwhich provide a substantially non-self-aggregating uniform heterogeneitythroughout the area of the films. Desirably, such films are producedthrough a selection of a polymer or combination of polymers that willprovide a desired viscosity, a film-forming process such as reverse rollcoating, and a controlled, and desirably rapid, drying process whichserves to maintain the uniform distribution of non-self-aggregatedcomponents without the necessary addition of gel formers or polyhydricalcohols and the like which appear to be required in the products andfor the processes of prior patents, such as the aforementioned Horstmannand Zerbe patents. Desirably, the films will also incorporatecompositions and methods of manufacture that substantially reduce oreliminate air in the film, thereby promoting uniformity in the finalfilm product.

SUMMARY OF THE INVENTION

In one aspect of the present invention there is provided an ingestiblefilm product containing a desired level of a pharmaceutical orbiological active component formed by the steps of:

(a) combining a water-soluble polymer, water and a pharmaceutical orbiological active component to form a material having a substantiallyuniform distribution of components;

(b) forming the material into a film;

(c) providing a conveyor surface having top and bottom sides;

(d) feeding the film onto the top side of the surface; and

(e) drying the film within about 10 minutes or fewer by applying heat tothe bottom side of the conveyor surface with substantially no hot aircurrents on the top side of the surface at a temperature above adegradation temperature of the pharmaceutical or biological activecomponent, wherein the degradation temperature is 70° C. or higher,

wherein the pharmaceutical or biological active component is maintainedat the desired level, and

wherein the water is present in the dried film at about 10% by weight ofthe film or less.

In another aspect of the present invention, there is provided aningestible film product containing a desired level of a pharmaceuticalor biological active component formed by the steps of:

(a) forming a master-batch premix of a water-soluble polymer and water;

(b) feeding a predetermined amount of the premix to at least one mixer;

(c) adding a pharmaceutical or biological active component to the atleast one mixer;

(d) mixing the pharmaceutical or biological active component and thepredetermined amount of the premix to form a material having asubstantially uniform distribution of components;

(e) forming the material into a film;

(f) providing a conveyor surface having top and bottom sides;

(g) feeding the film onto the top side of the surface; and

(h) drying the film by applying heat to the bottom side of the conveyorsurface at a temperature above a degradation temperature of thepharmaceutical or biological active component, wherein the degradationtemperature is 70° C. or higher,

wherein the drying step further comprises rapidly forming avisco-elastic film within about the first 4.0 minutes by applying heatto the bottom side of the surface in the absence of hot air currents onthe top side of the surface; and

drying the visco-elastic film to form a self-supporting ingestible film,

wherein the pharmaceutical or biological active component is maintainedat the desired level, and

wherein the water is present in the dried film at about 10% by weight ofthe film or less.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a side view of a package containing a unit dosage film ofthe present invention.

FIG. 2 shows a top view of two adjacently coupled packages containingindividual unit dosage forms of the present invention, separated by atearable perforation.

FIG. 3 shows a side view of the adjacently coupled packages of FIG. 2arranged in a stacked configuration.

FIG. 4 shows a perspective view of a dispenser for dispensing thepackaged unit dosage forms, dispenser containing the packaged unitdosage forms in a stacked configuration.

FIG. 5 is a schematic view of a roll of coupled unit dose packages ofthe present invention.

FIG. 6 is a schematic view of an apparatus suitable for preparation of apre-mix, addition of an active, and subsequent formation of the film.

FIG. 7 is a schematic view of an apparatus suitable for drying the filmsof the present invention.

FIG. 8 is a sequential representation of the drying process of thepresent invention.

FIG. 9 is a photographic representation of a film dried by conventionaldrying processes.

FIG. 10 is a photographic representation of a film dried by conventionaldrying processes.

FIG. 11 is a photographic representation of a film dried by conventionaldrying processes.

FIG. 12 is a photographic representation of a film dried by conventionaldrying processes.

FIG. 13 is a photographic representation of a film dried by conventionaldrying processes.

FIG. 14 is a photographic representation of a film dried by conventionaldrying processes.

FIG. 15 is a photographic representation of a film dried by conventionaldrying processes.

FIG. 16 is a photographic representation of a film dried by conventionaldrying processes.

FIG. 17 is a photographic representation of a film dried by theinventive drying process.

FIG. 18 is a photographic representation of a film containing fat coatedparticles dried by the inventive drying process.

FIG. 19 is a photographic representation of a film containing fat coatedparticles dried by the inventive drying process.

FIG. 20 is a photographic representation of a film containing fat coatedparticles dried by the inventive drying process.

FIG. 21 is a photographic representation of a film containing fat coatedparticles dried by the inventive drying process.

FIG. 22 is a photographic representation of a film containing fat coatedparticles dried by the inventive drying process.

FIG. 23 is a photographic representation of a film containing fat coatedparticles dried by the inventive drying process.

FIG. 24 is a photographic representation of a film containing fat coatedparticles dried by the inventive drying process.

FIG. 25 is a photographic representation of a film containing fat coatedparticles dried by the inventive drying process.

FIG. 26 is a photographic representation of fat coated particles not infilm, heated for 9 minutes at 80° C.

FIG. 27 is a photographic representation of fat coated particles not infilm, heated for 9 minutes at 80° C.

FIG. 28 is a photographic representation of fat coated particles at roomtemperature prior to processing.

FIG. 29 is a photographic representation of fat coated particles at roomtemperature prior to processing.

FIG. 30 is a photographic representation of fat coated particles at roomtemperature prior to processing.

FIG. 31 is a photographic representation of fat coated particles at roomtemperature prior to processing.

FIG. 32 is a graphical representation of a microarray on the blood of ahuman after ingestion by the human of a film of the present inventioncontaining a bovine derived protein.

FIG. 33 is a table of the data represented in the graph of FIG. 32.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention the term non-self-aggregatinguniform heterogeneity refers to the ability of the films of the presentinvention, which are formed from one or more components in addition to apolar solvent, to provide a substantially reduced occurrence of, i.e.little or no, aggregation or conglomeration of components within thefilm as is normally experienced when films are formed by conventionaldrying methods such as a high-temperature air-bath using a drying oven,drying tunnel, vacuum drier, or other such drying equipment. The termheterogeneity, as used in the present invention, includes films thatwill incorporate a single component, such as a polymer, as well ascombinations of components, such as a polymer and an active. Uniformheterogeneity includes the substantial absence of aggregates orconglomerates as is common in conventional mixing and heat dryingmethods used to form films.

Furthermore, the films of the present invention have a substantiallyuniform thickness, which is also not provided by the use of conventionaldrying methods used for drying water-based polymer systems. The absenceof a uniform thickness detrimentally affects uniformity of componentdistribution throughout the area of a given film.

The film products of the present invention are produced by a combinationof a properly selected polymer and a polar solvent, optionally includingan active ingredient as well as other fillers known in the art. Thesefilms provide a non-self-aggregating uniform heterogeneity of thecomponents within them by utilizing a selected casting or depositionmethod and a controlled drying process. Examples of controlled dryingprocesses include, but are not limited to, the use of the apparatusdisclosed in U.S. Pat. No. 4,631,837 to Magoon (“Magoon”), hereinincorporated by reference, as well as hot air impingement across thebottom substrate and bottom heating plates. Another drying technique forobtaining the films of the present invention is controlled drying, inthe absence of uncontrolled air currents, such as infrared and radiofrequency radiation (i.e. microwaves).

The objective of the drying process is to provide a method of drying thefilms that avoids complications, such as the noted “rippling” effect,that are associated with conventional drying methods and which initiallydry the upper surface of the film, trapping moisture inside. Inconventional oven drying methods, as the moisture trapped insidesubsequently evaporates, the top surface is altered by being ripped openand then reformed. These complications are avoided by the presentinvention, and a uniform film is provided by drying the bottom surfaceof the film first or otherwise preventing the formation of polymer filmformation (skin) on the top surface of the film prior to drying thedepth of the film. This may be achieved by applying heat to the bottomsurface of the film with substantially no top air flow, or alternativelyby the introduction of controlled microwaves to evaporate the water orother polar solvent within the film, again with substantially no top airflow. Yet alternatively, drying may be achieved by using balanced fluidflow, such as balanced air flow, where the bottom and top air flows arecontrolled to provide a uniform film. In such a case, the air flowdirected at the top of the film should not create a condition whichwould cause movement of particles present in the wet film, due to forcesgenerated by the air currents. Additionally, air currents directed atthe bottom of the film should desirably be controlled such that the filmdoes not lift up due to forces from the air. Uncontrolled air currents,either above or below the film, can create non-uniformity in the finalfilm products. The humidity level of the area surrounding the topsurface may also be appropriately adjusted to prevent premature closureor skinning of the polymer surface.

This manner of drying the films provides several advantages. Among theseare the faster drying times and a more uniform surface of the film, aswell as uniform distribution of components for any given area in thefilm. In addition, the faster drying time allows viscosity to quicklybuild within the film, further encouraging a uniform distribution ofcomponents and decrease in aggregation of components in the final filmproduct. Desirably, the drying of the film will occur within about tenminutes or fewer, or more desirably within about five minutes or fewer.

The present invention yields exceptionally uniform film products whenattention is paid to reducing the aggregation of the compositionalcomponents. By avoiding the introduction of and eliminating excessiveair in the mixing process, selecting polymers and solvents to provide acontrollable viscosity and by drying the film in a rapid manner from thebottom up, such films result.

The products and processes of the present invention rely on theinteraction among various steps of the production of the films in orderto provide films that substantially reduce the self-aggregation of thecomponents within the films. Specifically, these steps include theparticular method used to form the film, making the composition mixtureto prevent air bubble inclusions, controlling the viscosity of the filmforming composition and the method of drying the film. Moreparticularly, a greater viscosity of components in the mixture isparticularly useful when the active is not soluble in the selected polarsolvent in order to prevent the active from settling out. However, theviscosity must not be too great as to hinder or prevent the chosenmethod of casting, which desirably includes reverse roll coating due toits ability to provide a film of substantially consistent thickness.

In addition to the viscosity of the film or film-forming components ormatrix, there are other considerations taken into account by the presentinvention for achieving desirable film uniformity. For example, stablesuspensions are achieved which prevent solid (such as drug particles)sedimentation in non-colloidal applications. One approach provided bythe present invention is to balance the density of the particulate(ρ_(p)) and the liquid phase (ρ₁) and increase the viscosity of theliquid phase (μ). For an isolated particle, Stokes law relates theterminal settling velocity (Vo) of a rigid spherical body of radius (r)in a viscous fluid, as follows:

V _(o)=(2gr ^(r))(ρ_(p)−ρ₁)/9μ

At high particle concentrations, however, the local particleconcentration will affect the local viscosity and density. The viscosityof the suspension is a strong function of solids volume fraction, andparticle-particle and particle-liquid interactions will further hindersettling velocity.

Stokian analyses has shown that the incorporation of a third phase,dispersed air or nitrogen, for example, promotes suspension stability.Further, increasing the number of particles leads to a hindered settlingeffect based on the solids volume fraction. In dilute particlesuspensions, the rate of sedimentation, v, can be expressed as:

v/V _(o)=1/(1+κφ)

where κ=a constant, and φ is the volume fraction of the dispersed phase.More particles suspended in the liquid phase results in decreasedvelocity. Particle geometry is also an important factor since theparticle dimensions will affect particle-particle flow interactions.

Similarly, the viscosity of the suspension is dependent on the volumefraction of dispersed solids. For dilute suspensions of non-interactionspherical particles, an expression for the suspension viscosity can beexpressed as:

μ/μ_(o)=1+2.5φ

where μ_(o) is the viscosity of the continuous phase and φ is the solidsvolume fraction. At higher volume fractions, the viscosity of thedispersion can be expressed as

μ/μ_(o)=1+2.5φ+C ₁φ² +C ₂φ³+ . . .

where C is a constant.

The viscosity of the liquid phase is critical and is desirably modifiedby customizing the liquid composition to a viscoelastic non-Newtonianfluid with low yield stress values. This is the equivalent of producinga high viscosity continuous phase at rest. Formation of a viscoelasticor a highly structured fluid phase provides additional resistive forcesto particle sedimentation. Further, flocculation or aggregation can becontrolled minimizing particle-particle interactions. The net effectwould be the preservation of a homogeneous dispersed phase.

The addition of hydrocolloids to the aqueous phase of the suspensionincreases viscosity, may produce viscoelasticity and can impartstability depending on the type of hydrocolloid, its concentration andthe particle composition, geometry, size, and volume fraction. Theparticle size distribution of the dispersed phase needs to be controlledby selecting the smallest realistic particle size in the high viscositymedium, i.e., <500 μm. The presence of a slight yield stress or elasticbody at low shear rates may also induce permanent stability regardlessof the apparent viscosity. The critical particle diameter can becalculated from the yield stress values. In the case of isolatedspherical particles, the maximum shear stress developed in settlingthrough a medium of given viscosity can be given as

τ_(max)=3Vμ/2r

For pseudoplastic fluids, the viscosity in this shear stress regime maywell be the zero shear rate viscosity at the Newtonian plateau.

A stable suspension is an important characteristic for the manufactureof a pre-mix composition which is to be fed into the film castingmachinery film, as well as the maintenance of this stability in the wetfilm stage until sufficient drying has occurred to lock-in the particlesand matrix into a sufficiently solid form such that uniformity ismaintained. For viscoelastic fluid systems, a rheology that yieldsstable suspensions for extended time period, such as 24 hours, must bebalanced with the requirements of high-speed film casting operations. Adesirable property for the films is shear thinning or pseudoplasticity,whereby the viscosity decreases with increasing shear rate. Timedependent shear effects such as thixotropy are also advantageous.Structural recovery and shear thinning behavior are importantproperties, as is the ability for the film to self-level as it isformed.

The rheology requirements for the inventive compositions and films arequite severe. This is due to the need to produce a stable suspension ofparticles, for example 30-60 wt %, in a viscoelastic fluid matrix withacceptable viscosity values throughout a broad shear rate range. Duringmixing, pumping, and film casting, shear rates in the range of 10-10⁵sec.⁻¹ may be experienced and pseudoplasticity is the preferredembodiment.

In film casting or coating, rheology is also a defining factor withrespect to the ability to form films with the desired uniformity. Shearviscosity, extensional viscosity, viscoelasticity, structural recoverywill influence the quality of the film. As an illustrative example, theleveling of shear-thinning pseudoplastic fluids has been derived as

α^((n−1/n))=α_(o) ^((n−1/n))−((n−1)/(2n−1))(τ/K)^(1/n)(2π/λ)^((3+n)/n) h^((2n+1)/n) t

where α is the surface wave amplitude, α_(o) is the initial amplitude, λis the wavelength of the surface roughness, and both “n” and “K” areviscosity power law indices. In this example, leveling behavior isrelated to viscosity, increasing as n decreases, and decreasing withincreasing K.

Desirably, the films or film-forming compositions of the presentinvention have a very rapid structural recovery, i.e. as the film isformed during processing, it doesn't fall apart or become discontinuousin its structure and compositional uniformity. Such very rapidstructural recovery retards particle settling and sedimentation.Moreover, the films or film-forming compositions of the presentinvention are desirably shear-thinning pseudoplastic fluids. Such fluidswith consideration of properties, such as viscosity and elasticity,promote thin film formation and uniformity.

Thus, uniformity in the mixture of components depends upon numerousvariables. As described herein, viscosity of the components, the mixingtechniques and the rheological properties of the resultant mixedcomposition and wet casted film are important aspects of the presentinvention. Additionally, control of particle size and particle shape arefurther considerations. Desirably, the size of the particulate aparticle size of 150 microns or less, for example 100 microns or less.Moreover, such particles may be spherical, substantially spherical, ornon-spherical, such as irregularly shaped particles or ellipsoidallyshaped particles. Ellipsoidally shaped particles or ellipsoids aredesirable because of their ability to maintain uniformity in the filmforming matrix as they tend to settle to a lesser degree as compared tospherical particles.

A number of techniques may be employed in the mixing stage to preventbubble inclusions in the final film. To provide a composition mixturewith substantially no air bubble formation in the final product,anti-foaming or surface-tension reducing agents are employed.Additionally, the speed of the mixture is desirably controlled toprevent cavitation of the mixture in a manner which pulls air into themix. Finally, air bubble reduction can further be achieved by allowingthe mix to stand for a sufficient time for bubbles to escape prior todrying the film. Desirably, the inventive process first forms amasterbatch of film-forming components without active ingredients suchas drug particles or volatile materials such as flavor oils. The activesare added to smaller mixes of the masterbatch just prior to casting.Thus, the masterbatch pre-mix can be allowed to stand for a longer timewithout concern for instability in drug or other ingredients.

When the matrix is formed including the film-forming polymer and polarsolvent in addition to any additives and the active ingredient, this maybe done in a number of steps. For example, the ingredients may all beadded together or a pre-mix may be prepared. The advantage of a pre-mixis that all ingredients except for the active may be combined inadvance, with the active added just prior to formation of the film. Thisis especially important for actives that may degrade with prolongedexposure to water, air or another polar solvent.

FIG. 6 shows an apparatus 20 suitable for the preparation of a pre-mix,addition of an active and subsequent formation of a film. The pre-mix ormaster batch 22, which includes the film-forming polymer, polar solvent,and any other additives except a drug active is added to the masterbatch feed tank 24. The components for pre-mix or master batch 22 aredesirably formed in a mixer (not shown) prior to their addition into themaster batch feed tank 24. Then a pre-determined amount of the masterbatch is controllably fed via a first metering pump 26 and control valve28 to either or both of the first and second mixers, 30, 30′. Thepresent invention, however, is not limited to the use of two mixers, 30,30′, and any number of mixers may suitably be used. Moreover, thepresent invention is not limited to any particular sequencing of themixers 30, 30′, such as parallel sequencing as depicted in FIG. 6, andother sequencing or arrangements of mixers, such as series orcombination of parallel and series, may suitably be used. The requiredamount of the drug or other ingredient, such as a flavor, is added tothe desired mixer through an opening, 32, 32′, in each of the mixers,30, 30′. Desirably, the residence time of the pre-mix or master batch 22is minimized in the mixers 30, 30′. While complete dispersion of thedrug into the pre-mix or master batch 22 is desirable, excessiveresidence times may result in leaching or dissolving of the drug,especially in the case for a soluble drug. Thus, the mixers 30, 30′ areoften smaller, i.e. lower residence times, as compared to the primarymixers (not shown) used in forming the pre-mix or master batch 22. Afterthe drug has been blended with the master batch pre-mix for a sufficienttime to provide a uniform matrix, a specific amount of the uniformmatrix is then fed to the pan 36 through the second metering pumps, 34,34′. The metering roller 38 determines the thickness of the film 42 andapplies it to the application roller. The film 42 is finally formed onthe substrate 44 and carried away via the support roller 46.

While the proper viscosity uniformity in mixture and stable suspensionof particles, and casting method are important in the initial steps offorming the composition and film to promote uniformity, the method ofdrying the wet film is also important. Although these parameters andproperties assist uniformity initially, a controlled rapid dryingprocess ensures that the uniformity will be maintained until the film isdry.

The wet film is then dried using controlled bottom drying or controlledmicrowave drying, desirably in the absence of external air currents orheat on the top (exposed) surface of the film 48 as described herein.Controlled bottom drying or controlled microwave drying advantageouslyallows for vapor release from the film without the disadvantages of theprior art. Conventional convection air drying from the top is notemployed because it initiates drying at the top uppermost portion of thefilm, thereby forming a barrier against fluid flow, such as theevaporative vapors, and thermal flow, such as the thermal energy fordrying. Such dried upper portions serve as a barrier to further vaporrelease as the portions beneath are dried, which results in non-uniformfilms. As previously mentioned some top air flow can be used to aid thedrying of the films of the present invention, but it must not create acondition that would cause particle movement or a rippling effect in thefilm, both of which would result in non-uniformity. If top air isemployed, it is balanced with the bottom air drying to avoidnon-uniformity and prevent film lift-up on the carrier belt. A balancetop and bottom air flow may be suitable where the bottom air flowfunctions as the major source of drying and the top air flow is theminor source of drying. The advantage of some top air flow is to movethe exiting vapors away from the film thereby aiding in the overalldrying process. The use of any top air flow or top drying, however, mustbe balanced by a number of factors including, but not limited, torheological properties of the composition and mechanical aspects of theprocessing. Any top fluid flow, such as air, also must not overcome theinherent viscosity of the film-forming composition. In other words, thetop air flow cannot break, distort or otherwise physically disturb thesurface of the composition. Moreover, air velocities are desirably belowthe yield values of the film, i.e., below any force level that can movethe liquids in the film-forming compositions. For thin or low viscositycompositions, low air velocity must be used. For thick or high viscositycompositions, higher air velocities may be used. Furthermore, airvelocities are desirable low so as to avoid any lifting or othermovement of the film formed from the compositions.

Moreover, the films of the present invention may contain particles thatare sensitive to temperature, such as flavors, which may be volatile, ordrugs, which may have a low degradation temperature. In such cases, thedrying temperature may be decreased while increasing the drying time toadequately dry the uniform films of the present invention. Furthermore,bottom drying also tends to result in a lower internal film temperatureas compared to top drying. In bottom drying, the evaporating vapors morereadily carry heat away from the film as compared to top drying whichlowers the internal film temperature. Such lower internal filmtemperatures often result in decreased drug degradation and decreasedloss of certain volatiles, such as flavors.

During film preparation, it may be desirable to dry films at hightemperatures. High heat drying produces uniform films, and leads togreater efficiencies in film production. Films containing sensitiveactive components, however, may face degradation problems at hightemperatures. Degradation is the “decomposition of a compound . . .exhibiting well-defined intermediate products.” The American HeritageDictionary of the English Language (4^(th) ed. 2000). Degradation of anactive component is typically undesirable as it may cause instability,inactivity, and/or decreased potency of the active component. Forinstance, if the active component is a drug or bioactive material, thismay adversely affect the safety or efficacy of the final pharmaceuticalproduct. Additionally, highly volatile materials will tend to be quicklyreleased from this film upon exposure to conventional drying methods.

Degradation of an active component may occur through a variety ofprocesses, such as, hydrolysis, oxidation, and light degradation,depending upon the particular active component. Moreover, temperaturehas a significant effect on the rate of such reactions. The rate ofdegradation typically doubles for every 10° C. increase in temperature.Therefore, it is commonly understood that exposing an active componentto high temperatures will initiate and/or accelerate undesirabledegradation reactions.

Proteins are one category of useful active ingredients that willdegrade, denature, or otherwise become inactive when they are exposed tohigh temperatures for extended periods of time. Proteins serve a varietyof functions in the body such as enzymes, structural elements, hormonesand immunoglobulins. Examples of proteins include enzymes such aspancreatin, trypsin, pancrelipase, chymotrypsin, hyaluronidase,sutilains, streptokinaw, urokinase, altiplase, papain,bromelainsdiastase, structural elements such as collagen and albumin,hormones such as thyroliberin, gonadoliberin, adrenocorticottropin,corticotrophin, cosyntropin, sometrem, somatropion, prolactin,thyrotropin, somatostatin, vasopressin, felypressin, lypressin, insulin,glucagons, gastrin, pentagastrin, secretin,cholecystokinin-pancreozymin, and immunomodulators which may includepolysaccharides in addition to glycoproteins including cytokines whichare useful for the inhibition and prevention of malignant cell growthsuch as tumor growth. A suitable method for the production of someuseful glycoproteins is disclosed in U.S. Pat. No. 6,281,337 toCannon-Carlson, et al., which in incorporated herein in its entirety.

Temperatures that approach 100° C. will generally cause degradation ofproteins as well as nucleic acids. For example some glycoproteins willdegrade if exposed to a temperature of 70° C. for thirty minutes.Proteins from bovine extract are also known to degrade at such lowtemperatures. DNA also begins to denature at this temperature.

Applicants have discovered, however, that the films of the presentinvention may be exposed to high temperatures during the drying processwithout concern for degradation, loss of activity or excessiveevaporation due to the inventive process for film preparation andforming. In particular, the films may be exposed to temperatures thatwould typically lead to degradation, denaturization, or inactivity ofthe active component, without causing such problems. According to thepresent invention, the manner of drying may be controlled to preventdeleterious levels of heat from reaching the active component.

As discussed herein, the flowable mixture is prepared to be uniform incontent in accordance with the teachings of the present invention.Uniformity must be maintained as the flowable mass was formed into afilm and dried. During the drying process of the present invention,several factors produce uniformity within the film while maintaining theactive component at a safe temperature, i.e., below its degradationtemperature. First, the films of the present invention have an extremelyshort heat history, usually only on the order of minutes, so that totaltemperature exposure is minimized to the extent possible. The films arecontrollably dried to prevent aggregation and migration of components,as well as preventing heat build up within. Desirably, the films aredried from the bottom. Controlled bottom drying, as described herein,prevents the formation of a polymer film, or skin, on the top surface ofthe film. As heat is conducted from the film bottom upward, liquidcarrier, e.g., water, rises to the film surface. The absence of asurface skin permits rapid evaporation of the liquid carrier as thetemperature increases, and thus, concurrent evaporative cooling of thefilm. Due to the short heat exposure and evaporative cooling, the filmcomponents such as drag or volatile actives remain unaffected by hightemperatures. In contrast, skinning on the top surface traps liquidcarrier molecules of increased energy within the film, thereby causingthe temperature within the film to rise and exposing active componentsto high, potentially deleterious temperatures.

Second, thermal mixing occurs within the film due to bottom heating andabsence of surface skinning. Thermal mixing occurs via convectioncurrents in the film. As heat is applied to the bottom of the film, theliquid near the bottom increases in temperature, expands, and becomesless dense. As such, this hotter liquid rises and cooler liquid takesits place. While rising, the hotter liquid mixes with the cooler liquidand shares thermal energy with it, i.e., transfers heat. As the cyclerepeats, thermal energy is spread throughout the film.

Robust thermal mixing achieved by the controlled drying process of thepresent invention produces uniform heat diffusion throughout the film.In the absence of such thermal mixing, “hot spots” may develop. Pocketsof heat in the film result in the formation of particle aggregates ordanger areas within the film and subsequent non-uniformity. Theformation of such aggregates or agglomerations is undesirable because itleads to non-uniform films in which the active may be randomlydistributed. Such uneven distribution may lead to large differences inthe amount of active per film, which is problematic from a safety andefficacy perspective.

Furthermore, thermal mixing helps to maintain a lower overalltemperature inside the film. Although the film surfaces may be exposedto a temperature above that at which the active component degrades, thefilm interior may not reach this temperature. Due to this temperaturedifferential, the active does not degrade.

FIG. 8 is a sequential representation of the drying process of thepresent invention. After mechanical mixing, the film may be placed on aconveyor for continued thermal mixing during the drying process. At theoutset of the drying process, depicted in Section A, the film 1preferably is heated from the bottom 10 as it is travels via conveyor(not shown). Heat may be supplied to the film by a heating mechanism,such as, but not limited to, the dryer depicted in FIG. 7. As the filmis heated, the liquid carrier, or volatile (“V”), begins to evaporate,as shown by upward arrow 50. Thermal mixing also initiates as hotterliquid, depicted by arrow 30, rises and cooler liquid, depicted by arrow40, takes its place. Because no skin forms on the top surface 20 of thefilm 1, as shown in Section B the volatile liquid continues to evaporate50 and thermal mixing 30/40 continues to distribute thermal energythroughout the film. Once a sufficient amount of the volatile liquid hasevaporated, thermal mixing has produced uniform heat diffusionthroughout the film 1. The resulting dried film 1 is a visco-elasticsolid, as depicted in Section C. The components desirably are lockedinto a uniform distribution throughout the film. Although minor amountsof liquid carrier, i.e., water, may remain subsequent to formation ofthe visco-elastic, the film may be dried further without movement of theparticles, if desired.

Furthermore, particles or particulates may be added to the film-formingcomposition or matrix after the composition or matrix is cast into afilm. For example, particles may be added to the film 42 prior to thedrying of the film 42. Particles may be controllably metered to the filmand disposed onto the film through a suitable technique, such as throughthe use of a doctor blade (not shown) which is a device which marginallyor softly touches the surface of the film and controllably disposes theparticles onto the film surface. Other suitable, but non-limiting,techniques include the use of an additional roller to place theparticles on the film surface, spraying the particles onto the filmsurface, and the like. The particles may be placed on either or both ofthe opposed film surfaces, i.e., the top and/or bottom film surfaces.Desirably, the particles are securably disposed onto the film, such asbeing embedded into the film. Moreover, such particles are desirably notfully encased or fully embedded into the film, but remain exposed to thesurface of the film, such as in the case where the particles arepartially embedded or partially encased.

The particles may be any useful organoleptic agent, cosmetic agent,pharmaceutical agent, or combinations thereof. Desirably, thepharmaceutical agent is a taste-masked or a controlled-releasepharmaceutical agent. Useful organoleptic agents include flavors andsweeteners. Useful cosmetic agents include breath freshening ordecongestant agents, such as menthol, including menthol crystals.

Although the inventive process is not limited to any particularapparatus for the above-described desirable drying, one particularuseful drying apparatus 50 is depicted in FIG. 7. Drying apparatus 50 isa nozzle arrangement for directing hot fluid, such as but not limited tohot air, towards the bottom of the film 42 which is disposed onsubstrate 44. Hot air enters the entrance end 52 of the drying apparatusand travels vertically upward, as depicted by vectors 54, towards airdeflector 56. The air deflector 56 redirects the air movement tominimize upward force on the film 42. As depicted in FIG. 7, the air istangentially directed, as indicated by vectors 60 and 60′, as the airpasses by air deflector 56 and enters and travels through chamberportions 58 and 58′ of the drying apparatus 50. With the hot air flowbeing substantially tangential to the film 42, lifting of the film as itis being dried is thereby minimized. While the air deflector 56 isdepicted as a roller, other devices and geometries for deflecting air orhot fluid may suitable be used. Furthermore, the exit ends 62 and 62′ ofthe drying apparatus 50 are flared downwardly. Such downward flaringprovides a downward force or downward velocity vector, as indicated byvectors 64 and 64′, which tend to provide a pulling or drag effect ofthe film 42 to prevent lifting of the film 42. Lifting of the film 42may not only result in non-uniformity in the film or otherwise, but mayalso result in non-controlled processing of the film 42 as the film 42and/or substrate 44 lift away from the processing equipment.

Monitoring and control of the thickness of the film also contributes tothe production of a uniform film by providing a film of uniformthickness. The thickness of the film may be monitored with gauges suchas Beta Gauges. A gauge may be coupled to another gauge at the end ofthe drying apparatus, i.e. drying oven or tunnel, to communicate throughfeedback loops to control and adjust the opening in the coatingapparatus, resulting in control of uniform film thickness.

The film products are generally formed by combining a properly selectedpolymer and polar solvent, as well as any active ingredient or filler asdesired. Desirably, the solvent content of the combination is at leastabout 30% by weight of the total combination. The matrix formed by thiscombination is formed into a film, desirably by roll coating, and thendried, desirably by a rapid and controlled drying process to maintainthe uniformity of the film, more specifically, a non-self-aggregatinguniform heterogeneity. The resulting film will desirably contain lessthan about 10% by weight solvent, more desirably less than about 8% byweight solvent, even more desirably less than about 6% by weight solventand most desirably less than about 2%. The solvent may be water, a polarorganic solvent including, but not limited to, ethanol, isopropanol,acetone, methylene chloride, or any combination thereof.

Consideration of the above discussed parameters, such as but not limitedto rheology properties, viscosity, mixing method, casting method anddrying method, also impact material selection for the differentcomponents of the present invention. Furthermore, such considerationwith proper material selection provides the compositions of the presentinvention, including a pharmaceutical and/or cosmetic dosage form orfilm product having no more than a 10% variance of a pharmaceuticaland/or cosmetic active per unit area. In other words, the uniformity ofthe present invention is determined by the presence of no more than a10% by weight of pharmaceutical and/or cosmetic variance throughout thematrix. Desirably, the variance is less than 5% by weight, less than 2%by weight, less than 1% by weight, or less than 0.5% by weight.

Film-Forming Polymers

The polymer may be water soluble, water swellable, water insoluble, or acombination of one or more either water soluble, water swellable orwater insoluble polymers. The polymer may include cellulose or acellulose derivative. Specific examples of useful water soluble polymersinclude, but are not limited to, pullulan, hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium aginate,polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum,arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinylcopolymers, starch, gelatin, and combinations thereof. Specific examplesof useful water insoluble polymers include, but are not limited to,ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetatephthalate, hydroxypropyl methyl cellulose phthalate and combinationsthereof.

As used herein the phrase “water soluble polymer” and variants thereofrefer to a polymer that is at least partially soluble in water, anddesirably fully or predominantly soluble in water, or absorbs water.Polymers that absorb water are often referred to as being waterswellable polymers. The materials useful with the present invention maybe water soluble or water swellable at room temperature and othertemperatures, such as temperatures exceeding room temperature. Moreover,the materials may be water soluble or water swellable at pressures lessthan atmospheric pressure. Desirably, the water soluble polymers arewater soluble or water swellable having at least 20 percent by weightwater uptake. Water swellable polymers having a 25 or greater percent byweight water uptake are also useful. Films or dosage forms of thepresent invention formed from such water soluble polymers are desirablysufficiently water soluble to be dissolvable upon contact with bodilyfluids.

Other polymers useful for incorporation into the films of the presentinvention include biodegradable polymers, copolymers, block polymers andcombinations thereof. Among the known useful polymers or polymer classeswhich meet the above criteria are: poly(glycolic acid) (PGA),poly(lactic acid) (PLA), polydioxanoes, polyoxalates, poly(α-esters),polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters),polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates,polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymersthereof. Additional useful polymers include, stereopolymers of L- andD-lactic acid, copolymers of bis(p-carboxyphenoxy) propane acid andsebacic acid, sebacic acid copolymers, copolymers of caprolactone,poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol copolymers,copolymers of polyurethane and (poly(lactic acid), copolymers ofpolyurethane and poly(lactic acid), copolymers of α-amino acids,copolymers of α-amino acids and caproic acid, copolymers of α-benzylglutamate and polyethylene glycol, copolymers of succinate andpoly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixturesthereof. Binary and ternary systems are contemplated.

Other specific polymers useful include those marketed under the Medisorband Biodel trademarks. The Medisorb materials are marketed by the DupontCompany of Wilmington, Del. and are generically identified as a“lactide/glycolide co-polymer” containing “propanoic acid,2-hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid.” Foursuch polymers include lactide/glycolide 100 L, believed to be 100%lactide having a melting point within the range of 338°-347° F.(170°-175° C.); lactide/glycolide 100 L, believed to be 100% glycolidehaving a melting point within the range of 437°-455° F. (225°-235° C.);lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolidewith a melting point within the range of 338°-347° F. (170°-175° C.);and lactide/glycolide 50/50, believed to be a copolymer of 50% lactideand 50% glycolide with a melting point within the range of 338°-347° F.(170°-175° C.).

The Biodel materials represent a family of various polyanhydrides whichdiffer chemically.

Although a variety of different polymers may be used, it is desired toselect polymers to provide a desired viscosity of the mixture prior todrying. For example, if the active or other components are not solublein the selected solvent, a polymer that will provide a greater viscosityis desired to assist in maintaining uniformity. On the other hand, ifthe components are soluble in the solvent, a polymer that provides alower viscosity may be preferred.

The polymer plays an important role in affecting the viscosity of thefilm. Viscosity is one property of a liquid that controls the stabilityof the active in an emulsion, a colloid or a suspension. Generally theviscosity of the matrix will vary from about 400 cps to about 100,000cps, preferably from about 800 cps to about 60,000 cps, and mostpreferably from about 1,000 cps to about 40,000 cps. Desirably, theviscosity of the film-forming matrix will rapidly increase uponinitiation of the drying process.

The viscosity may be adjusted based on the selected active depending onthe other components within the matrix. For example, if the component isnot soluble within the selected solvent, a proper viscosity may beselected to prevent the component from settling which would adverselyaffect the uniformity of the resulting film. The viscosity may beadjusted in different ways. To increase viscosity of the film matrix,the polymer may be chosen of a higher molecular weight or crosslinkersmay be added, such as salts of calcium, sodium and potassium. Theviscosity may also be adjusted by adjusting the temperature or by addinga viscosity increasing component. Components that will increase theviscosity or stabilize the emulsion/suspension include higher molecularweight polymers and polysaccharides and gums, which include withoutlimitation, alginate, carrageenan, hydroxypropyl methyl cellulose,locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan gumand combinations thereof.

It has also been observed that certain polymers which when used alonewould ordinarily require a plasticizer to achieve a flexible film, canbe combined without a plasticizer and yet achieve flexible films. Forexample, HPMC and HPC when used in combination provide a flexible,strong film with the appropriate plasticity and elasticity formanufacturing and storage. No additional plasticizer or polyalcohol isneeded for flexibility.

Controlled Release Films

The term “controlled release” is intended to mean the release of activeat a pre-selected or desired rate. This rate will vary depending uponthe application. Desirable rates include fast or immediate releaseprofiles as well as delayed, sustained or sequential release.Combinations of release patterns, such as initial spiked releasefollowed by lower levels of sustained release of active arecontemplated. Pulsed drug releases are also contemplated.

The polymers that are chosen for the films of the present invention mayalso be chosen to allow for controlled disintegration of the active.This may be achieved by providing a substantially water insoluble filmthat incorporates an active that will be released from the film overtime. This may be accomplished by incorporating a variety of differentsoluble or insoluble polymers and may also include biodegradablepolymers in combination. Alternatively, coated controlled release activeparticles may be incorporated into a readily soluble film matrix toachieve the controlled release property of the active inside thedigestive system upon consumption.

Films that provide a controlled release of the active are particularlyuseful for buccal, gingival, sublingual and vaginal applications. Thefilms of the present invention are particularly useful where mucosalmembranes or mucosal fluid is present due to their ability to readilywet and adhere to these areas.

The convenience of administering a single dose of a medication whichreleases active ingredients in a controlled fashion over an extendedperiod of time as opposed to the administration of a number of singledoses at regular intervals has long been recognized in thepharmaceutical arts. The advantage to the patient and clinician inhaving consistent and uniform blood levels of medication over anextended period of time are likewise recognized. The advantages of avariety of sustained release dosage forms are well known. However, thepreparation of a film that provides the controlled release of an activehas advantages in addition to those well-known for controlled releasetablets. For example, thin films are difficult to inadvertently aspirateand provide an increased patient compliance because they need not beswallowed like a tablet. Moreover, certain embodiments of the inventivefilms are designed to adhere to the buccal cavity and tongue, where theycontrollably dissolve. Furthermore, thin films may not be crushed in themanner of controlled release tablets which is a problem leading to abuseof drugs such as Oxycontin.

The actives employed in the present invention may be incorporated intothe film compositions of the present invention in a controlled releaseform. For example, particles of drug may be coated with polymers such asethyl cellulose or polymethacrylate, commercially available under brandnames such as Aquacoat ECD and Eudragit E-100, respectively. Solutionsof drug may also be absorbed on such polymer materials and incorporatedinto the inventive film compositions. Other components such as fats andwaxes, as well as sweeteners and/or flavors may also be employed in suchcontrolled release compositions.

The actives may be taste-masked prior to incorporation into the filmcomposition, as set forth in co-pending PCT application titled, UniformFilms For Rapid Dissolve Dosage Form Incorporating Taste-MaskingCompositions, (based on U.S. Provisional Application No. Express MailLabel No.: EU552991605 US of the same title, filed Sep. 27, 2003,attorney docket No. 1199-15P) the entire subject matter of which isincorporated by reference herein.

Actives

When an active is introduced to the film, the amount of active per unitarea is determined by the uniform distribution of the film. For example,when the films are cut into individual dosage forms, the amount of theactive in the dosage form can be known with a great deal of accuracy.This is achieved because the amount of the active in a given area issubstantially identical to the amount of active in an area of the samedimensions in another part of the film. The accuracy in dosage isparticularly advantageous when the active is a medicament, i.e. a drug.

The active components that may be incorporated into the films of thepresent invention include, without limitation pharmaceutical andcosmetic actives, drugs, medicaments, antigens or allergens such asragweed pollen, spores, microorganisms, seeds, mouthwash components,flavors, fragrances, enzymes, preservatives, sweetening agents,colorants, spices, vitamins and combinations thereof.

A wide variety of medicaments, bioactive active substances andpharmaceutical compositions may be included in the dosage forms of thepresent invention. Examples of useful drugs include ace-inhibitors,antianginal drugs, anti-arrhythmias, anti-asthmatics,anti-cholesterolemics, analgesics, anesthetics, anti-convulsants,anti-depressants, anti-diabetic agents, anti-diarrhea preparations,antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatoryagents, anti-lipid agents, anti-manics, anti-nauseants, anti-strokeagents, anti-thyroid preparations, anti-tumor drugs, anti-viral agents,acne drugs, alkaloids, amino acid preparations, anti-tussives,anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemicand non-systemic anti-infective agents, anti-neoplastics,anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants,biological response modifiers, blood modifiers, bone metabolismregulators, cardiovascular agents, central nervous system stimulates,cholinesterase inhibitors, contraceptives, decongestants, dietarysupplements, dopamine receptor agonists, endometriosis managementagents, enzymes, erectile dysfunction therapies, fertility agents,gastrointestinal agents, homeopathic remedies, hormones, hypercalcemiaand hypocalcemia management agents, immunomodulators,immunosuppressives, migraine preparations, motion sickness treatments,muscle relaxants, obesity management agents, osteoporosis preparations,oxytocics, parasympatholytics, parasympathomimetics, prostaglandins,psychotherapeutic agents, respiratory agents, sedatives, smokingcessation aids, sympatholytics, tremor preparations, urinary tractagents, vasodilators, laxatives, antacids, ion exchange resins,anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents,anti-ulcer agents, anti-inflammatory substances, coronary dilators,cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants,anti-hypertensive drugs, vasoconstrictors, migraine treatments,antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs,anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics,anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- andhypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics,anti-spasmodics, terine relaxants, anti-obesity drugs, erythropoieticdrugs, anti-asthmatics, cough suppressants, mucolytics, DNA and geneticmodifying drugs, and combinations thereof.

Examples of medicating active ingredients contemplated for use in thepresent invention include antacids, H₂-antagonists, and analgesics. Forexample, antacid dosages can be prepared using the ingredients calciumcarbonate alone or in combination with magnesium hydroxide, and/oraluminum hydroxide. Moreover, antacids can be used in combination withH₂-antagonists.

Analgesics include opiates and opiate derivatives, such as oxycodone(available as Oxycontin®), ibuprofen, aspirin, acetaminophen, andcombinations thereof that may optionally include caffeine.

Other preferred drugs for other preferred active ingredients for use inthe present invention include anti-diarrheals such as immodium AD,anti-histamines, anti-tussives, decongestants, vitamins, and breathfresheners. Common drugs used alone or in combination for colds, pain,fever, cough, congestion, runny nose and allergies, such asacetaminophen, chlorpheniramine maleate, dextromethorphan,pseudoephedrine HCl and diphenhydramine may be included in the filmcompositions of the present invention.

Also contemplated for use herein are anxiolytics such as alprazolam(available as Xanax®); anti-psychotics such as clozopin (available asClozaril®) and haloperidol (available as Haldol®); non-steroidalanti-inflammatories (NSAID's) such as dicyclofenacs (available asVoltaren®) and etodolac (available as Lodine®), anti-histamines such asloratadine (available as Claritin®), astemizole (available asHismanal™), nabumetone (available as Relafen®), and Clemastine(available as Tavist®); anti-emetics such as granisetron hydrochloride(available as Kytril®) and nabilone (available as Cesamet™);bronchodilators such as Bentolin®, albuterol sulfate (available asProventil®); anti-depressants such as fluoxetine hydrochloride(available as Prozac®), sertraline hydrochloride (available as Zoloft®),and paroxtine hydrochloride (available as Paxil®); anti-migraines suchas Imigra®, ACE-inhibitors such as enalaprilat (available as Vasotec®),captopril (available as Capoten®) and lisinopril (available asZestril®); anti-Alzheimer's agents, such as nicergoline; andCa^(H)-antagonists such as nifedipine (available as Procardia® andAdalat®), and verapamil hydrochloride (available as Calan®).

Erectile dysfunction therapies include, but are not limited to, drugsfor facilitating blood flow to the penis, and for effecting autonomicnervous activities, such as increasing parasympathetic (cholinergic) anddecreasing sympathetic (adrenersic) activities. Useful non-limitingdrugs include sildenafils, such as Viagra®, tadalafils, such as Cialis®,vardenafils, apomorphines, such as Uprima®, yohimbine hydrochloridessuch as Aphrodyne®, and alprostadils such as Caverject®.

The popular H₂-antagonists which are contemplated for use in the presentinvention include cimetidine, ranitidine hydrochloride, famotidine,nizatidien, ebrotidine, mifentidine, roxatidine, pisatidine andaceroxatidine.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, bismuthsubsilysilate, calcium carbonate, calcium phosphate, citrate ion (acidor salt), amino acetic acid, hydrate magnesium aluminate sulfate,magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesiumglycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate,milk solids, aluminum mono-ordibasic calcium phosphate, tricalciumphosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate,magnesium aluminosilicates, tartaric acids and salts.

The pharmaceutically active agents employed in the present invention mayinclude allergens or antigens, such as, but not limited to, plantpollens from grasses, trees, or ragweed; animal danders, which are tinyscales shed from the skin and hair of cats and other furred animals;insects, such as house dust mites, bees, and wasps; and drugs, such aspenicillin.

An anti-oxidant may also be added to the film to prevent the degradationof an active, especially where the active is photosensitive.

Cosmetic active agents may include breath freshening compounds likementhol, other flavors or fragrances, especially those used for oralhygiene, as well as actives used in dental and oral cleansing such asquaternary ammonium bases. The effect of flavors may be enhanced usingflavor enhancers like tartaric acid, citric acid, vanillin, or the like.

Also color additives can be used in preparing the films. Such coloradditives include food, drug and cosmetic colors (FD&C), drug andcosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).These colors are dyes, their corresponding lakes, and certain naturaland derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

Other examples of coloring agents include known azo dyes, organic orinorganic pigments, or coloring agents of natural origin. Inorganicpigments are preferred, such as the oxides or iron or titanium, theseoxides, being added in concentrations ranging from about 0.001 to about10%, and preferably about 0.5 to about 3%, based on the weight of allthe components.

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationsthereof. A non-limiting representative list of examples includes mintoils, cocoa, and citrus oils such as lemon, orange, grape, lime andgrapefruit and fruit essences including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot or other fruitflavors.

The films containing flavorings may be added to provide a hot or coldflavored drink or soup. These flavorings include, without limitation,tea and soup flavorings such as beef and chicken.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin),combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and combinationsthereof; saccharin and its various salts such as the sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; sugar alcohols such as sorbitol, mannitol,xylitol, and the like. Also contemplated are hydrogenated starchhydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof, and natural intensive sweeteners, such as Lo Han Kuo.Other sweeteners may also be used.

When the active is combined with the polymer in the solvent, the type ofmatrix that is formed depends on the solubilities of the active and thepolymer. If the active and/or polymer are soluble in the selectedsolvent, this may form a solution. However, if the components are notsoluble, the matrix may be classified as an emulsion, a colloid, or asuspension.

Dosages

The film products of the present invention are capable of accommodatinga wide range of amounts of the active ingredient. The films are capableof providing an accurate dosage amount (determined by the size of thefilm and concentration of the active in the original polymer/watercombination) regardless of whether the required dosage is high orextremely low. Therefore, depending on the type of active orpharmaceutical composition that is incorporated into the film, theactive amount may be as high as about 300 mg, desirably up to about 150mg or as low as the microgram range, or any amount therebetween.

The film products and methods of the present invention are well suitedfor high potency, low dosage drugs. This is accomplished through thehigh degree of uniformity of the films. Therefore, low dosage drugs,particularly more potent racemic mixtures of actives are desirable.

Anti-Foaming and De-Foaming Compositions

Anti-foaming and/or de-foaming components may also be used with thefilms of the present invention. These components aid in the removal ofair, such as entrapped air, from the film-forming compositions. Asdescribed above, such entrapped air may lead to non-uniform films.Simethicone is one particularly useful anti-foaming and/or de-foamingagent. The present invention, however, is not so limited and otheranti-foam and/or de-foaming agents may suitable be used.

Simethicone is generally used in the medical field as a treatment forgas or colic in babies. Simethicone is a mixture of fully methylatedlinear siloxane polymers containing repeating units ofpolydimethylsiloxane which is stabilized with trimethylsiloxyend-blocking unites, and silicon dioxide. It usually contains 90.5-99%polymethylsiloxane and 4-7% silicon dioxide. The mixture is a gray,translucent, viscous fluid which is insoluble in water.

When dispersed in water, simethicone will spread across the surface,forming a thin film of low surface tension. In this way, simethiconereduces the surface tension of bubbles air located in the solution, suchas foam bubbles, causing their collapse. The function of simethiconemimics the dual action of oil and alcohol in water. For example, in anoily solution any trapped air bubbles will ascend to the surface anddissipate more quickly and easily, because an oily liquid has a lighterdensity compared to a water solution. On the other hand, analcohol/water mixture is known to lower water density as well as lowerthe water's surface tension. So, any air bubbles trapped inside thismixture solution will also be easily dissipated. Simethicone solutionprovides both of these advantages. It lowers the surface energy of anyair bubbles that trapped inside the aqueous solution, as well aslowering the surface tension of the aqueous solution. As the result ofthis unique functionality, simethicone has an excellent anti-foamingproperty that can be used for physiological processes (anti-gas instomach) as well as any for external processes that require the removalof air bubbles from a product.

In order to prevent the formation of air bubbles in the films of thepresent invention, the mixing step can be performed under vacuum.However, as soon as the mixing step is completed, and the film solutionis returned to the normal atmosphere condition, air will bere-introduced into or contacted with the mixture. In many cases, tinyair bubbles will be again trapped inside this polymeric viscoussolution. The incorporation of simethicone into the film-formingcomposition either substantially reduces or eliminates the formation ofair bubbles.

Simethicone may be added to the film-forming mixture as an anti-foamingagent in an amount from about 0.01 weight percent to about 5.0 weightpercent, more desirably from about 0.05 weight percent to about 2.5weight percent, and most desirably from about 0.1 weight percent toabout 1.0 weight percent.

Optional Components

A variety of other components and fillers may also be added to the filmsof the present invention. These may include, without limitation,surfactants; plasticizers which assist in compatibilizing the componentswithin the mixture; polyalcohols; anti-foaming agents, such assilicone-containing compounds, which promote a smoother film surface byreleasing oxygen from the film; and thermo-setting gels such as pectin,carageenan, and gelatin, which help in maintaining the dispersion ofcomponents.

The variety of additives that can be incorporated into the inventivecompositions may provide a variety of different functions. Examples ofclasses of additives include excipients, lubricants, buffering agents,stabilizers, blowing agents, pigments, coloring agents, fillers, bulkingagents, sweetening agents, flavoring agents, fragrances, releasemodifiers, adjuvants, plasticizers, flow accelerators, mold releaseagents, polyols, granulating agents, diluents, binders, buffers,absorbents, glidants, adhesives, anti-adherents, acidulants, softeners,resins, demulcents, solvents, surfactants, emulsifiers, elastomers andmixtures thereof. These additives may be added with the activeingredient(s).

Useful additives include, for example, gelatin, vegetable proteins suchas sunflower protein, soybean proteins, cotton seed proteins, peanutproteins, grape seed proteins, whey proteins, whey protein isolates,blood proteins, egg proteins, acrylated proteins, water-solublepolysaccharides such as alginates, carrageenans, guar gum, agar-agar,xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gumkaraya, gum tragancanth), pectin, water-soluble derivatives ofcellulose: alkylcelluloses hydroxyalkylcelluloses andhydroxyalkylalkylcelluloses, such as methylcelulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxyethylmethylcellulose, hydroxypropylmethylcellulose,hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcelluloseesters such as cellulose acetate phthalate (CAP),hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses,carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such ascarboxymethylcellulose and their alkali metal salts; water-solublesynthetic polymers such as polyacrylic acids and polyacrylic acidesters, polymethacrylic acids and polymethacrylic acid esters,polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP),polyvinylpyrrolidone (PVP), PVY/vinyl acetate copolymer, andpolycrotonic acids; also suitable are phthalated gelatin, gelatinsuccinate, crosslinked gelatin, shellac, water soluble chemicalderivatives of starch, cationically modified acrylates and methacrylatespossessing, for example, a tertiary or quaternary amino group, such asthe diethylaminoethyl group, which may be quaternized if desired; andother similar polymers.

Such extenders may optionally be added in any desired amount desirablywithin the range of up to about 80%, desirably about 3% to 50% and moredesirably within the range of 3% to 20% based on the weight of allcomponents.

Further additives may be inorganic fillers, such as the oxides ofmagnesium aluminum, silicon, titanium, etc. desirably in a concentrationrange of about 0.02% to about 3% by weight and desirably about 0.02% toabout 1% based on the weight of all components.

Further examples of additives are plasticizers which includepolyalkylene oxides, such as polyethylene glycols, polypropyleneglycols, polyethylene-propylene glycols, organic plasticizers with lowmolecular weights, such as glycerol, glycerol monoacetate, diacetate ortriacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol,sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributylcitrate, and the like, added in concentrations ranging from about 0.5%to about 30%, and desirably ranging from about 0.5% to about 20% basedon the weight of the polymer.

There may further be added compounds to improve the flow properties ofthe starch material such as animal or vegetable fats, desirably in theirhydrogenated form, especially those which are solid at room temperature.These fats desirably have a melting point of 50° C. or higher. Preferredare tri-glycerides with C₁₂-, C₁₄-, C₁₆-, C₁₈-, C₂₀- and C₂₂-fattyacids. These fats can be added alone without adding extenders orplasticizers and can be advantageously added alone or together withmono- and/or di-glycerides or phosphatides, especially lecithin. Themono- and di-glycerides are desirably derived from the types of fatsdescribed above, i.e. with C₁₂-, C₁₄-, C₁₆-, C₁₈-, C₂₀- and C₂₂-fattyacids.

The total amounts used of the fats, mono-, di-glycerides and/orlecithins are up to about 5% and preferably within the range of about0.5% to about 2% by weight of the total composition

It is further useful to add silicon dioxide, calcium silicate, ortitanium dioxide in a concentration of about 0.02% to about 1% by weightof the total composition. These compounds act as texturizing agents.

These additives are to be used in amounts sufficient to achieve theirintended purpose. Generally, the combination of certain of theseadditives will alter the overall release profile of the activeingredient and can be used to modify, i.e. impede or accelerate therelease.

Lecithin is one surface active agent for use in the present invention.Lecithin can be included in the feedstock in an amount of from about0.25% to about 2.00% by weight. Other surface active agents, i.e.surfactants, include, but are not limited to, cetyl alcohol, sodiumlauryl sulfate, the Spans™ and Tweens™ which are commercially availablefrom ICI Americas, Inc. Ethoxylated oils, including ethoxylated castoroils, such as Cremophor® EL which is commercially available from BASF,are also useful. Carbowax™ is yet another modifier which is very usefulin the present invention. Tweens™ or combinations of surface activeagents may be used to achieve the desired hydrophilic-lipophilic balance(“HLB”). The present invention, however, does not require the use of asurfactant and films or film-forming compositions of the presentinvention may be essentially free of a surfactant while still providingthe desirable uniformity features of the present invention.

As additional modifiers which enhance the procedure and product of thepresent invention are identified, Applicants intend to include all suchadditional modifiers within the scope of the invention claimed herein.

Other ingredients include binders which contribute to the ease offormation and general quality of the films. Non-limiting examples ofbinders include starches, pregelatinize starches, gelatin,polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose,ethylcellulose, polyacrylamides, polyvinyloxoazolidone, andpolyvinylalcohols.

Forming the Film

The films of the present invention must be formed into a sheet prior todrying. After the desired components are combined to form amulti-component matrix, including the polymer, water, and an active orother components as desired, the combination is formed into a sheet orfilm, by any method known in the art such as extrusion, coating,spreading, casting or drawing the multi-component matrix. If amulti-layered film is desired, this may be accomplished by co-extrudingmore than one combination of components which may be of the same ordifferent composition. A multi-layered film may also be achieved bycoating, spreading, or casting a combination onto an already formed filmlayer.

Although a variety of different film-forming techniques may be used, itis desirable to select a method that will provide a flexible film, suchas reverse roll coating. The flexibility of the film allows for thesheets of film to be rolled and transported for storage or prior tobeing cut into individual dosage forms. Desirably, the films will alsobe self-supporting or in other words able to maintain their integrityand structure in the absence of a separate support. Furthermore, thefilms of the present invention may be selected of materials that areedible or ingestible.

Coating or casting methods are particularly useful for the purpose offorming the films of the present invention. Specific examples includereverse roll coating, gravure coating, immersion or dip coating,metering rod or meyer bar coating, slot die or extrusion coating, gap orknife over roll coating, air knife coating, curtain coating, orcombinations thereof, especially when a multi-layered film is desired.

Roll coating, or more specifically reverse roll coating, is particularlydesired when forming films in accordance with the present invention.This procedure provides excellent control and uniformity of theresulting films, which is desired in the present invention. In thisprocedure, the coating material is measured onto the applicator rollerby the precision setting of the gap between the upper metering rollerand the application roller below it. The coating is transferred from theapplication roller to the substrate as it passes around the supportroller adjacent to the application roller. Both three roll and four rollprocesses are common.

The gravure coating process relies on an engraved roller running in acoating bath, which fills the engraved dots or lines of the roller withthe coating material. The excess coating on the roller is wiped off by adoctor blade and the coating is then deposited onto the substrate as itpasses between the engraved roller and a pressure roller.

Offset Gravure is common, where the coating is deposited on anintermediate roller before transfer to the substrate.

In the simple process of immersion or dip coating, the substrate isdipped into a bath of the coating, which is normally of a low viscosityto enable the coating to run back into the bath as the substrateemerges.

In the metering rod coating process, an excess of the coating isdeposited onto the substrate as it passes over the bath roller. Thewire-wound metering rod, sometimes known as a Meyer Bar, allows thedesired quantity of the coating to remain on the substrate. The quantityis determined by the diameter of the wire used on the rod.

In the slot die process, the coating is squeezed out by gravity or underpressure through a slot and onto the substrate. If the coating is 100%solids, the process is termed “Extrusion” and in this case, the linespeed is frequently much faster than the speed of the extrusion. Thisenables coatings to be considerably thinner than the width of the slot.

The gap or knife over roll process relies on a coating being applied tothe substrate which then passes through a “gap” between a “knife” and asupport roller. As the coating and substrate pass through, the excess isscraped off.

Air knife coating is where the coating is applied to the substrate andthe excess is “blown off” by a powerful jet from the air knife. Thisprocedure is useful for aqueous coatings.

In the curtain coating process, a bath with a slot in the base allows acontinuous curtain of the coating to fall into the gap between twoconveyors. The object to be coated is passed along the conveyor at acontrolled speed and so receives the coating on its upper face.

Drying the Film

The drying step is also a contributing factor with regard to maintainingthe uniformity of the film composition. A controlled drying process isparticularly important when, in the absence of a viscosity increasingcomposition or a composition in which the viscosity is controlled, forexample by the selection of the polymer, the components within the filmmay have an increased tendency to aggregate or conglomerate. Analternative method of forming a film with an accurate dosage, that wouldnot necessitate the controlled drying process, would be to cast thefilms on a predetermined well. With this method, although the componentsmay aggregate, this will not result in the migration of the active to anadjacent dosage form, since each well may define the dosage unit per se.

When a controlled or rapid drying process is desired, this may bethrough a variety of methods. A variety of methods may be used includingthose that require the application of heat. The liquid carriers areremoved from the film in a manner such that the uniformity, or morespecifically, the non-self-aggregating uniform heterogeneity, that isobtained in the wet film is maintained.

Desirably, the film is dried from the bottom of the film to the top ofthe film. Desirably, substantially no air flow is present across the topof the film during its initial setting period, during which a solid,visco-elastic structure is formed. This can take place within the firstfew minutes, e.g. about the first 0.5 to about 4.0 minutes of the dryingprocess. Controlling the drying in this manner, prevents the destructionand reformation of the film's top surface, which results fromconventional drying methods. This is accomplished by forming the filmand placing it on the top side of a surface having top and bottom sides.Then, heat is initially applied to the bottom side of the film toprovide the necessary energy to evaporate or otherwise remove the liquidcarrier. The films dried in this manner dry more quickly and evenly ascompared to air-dried films, or those dried by conventional dryingmeans. In contrast to an air-dried film that dries first at the top andedges, the films dried by applying heat to the bottom dry simultaneouslyat the center as well as at the edges. This also prevents settling ofingredients that occurs with films dried by conventional means.

The temperature at which the films are dried is about 100° C. or less,desirably about 90° C. or less, and most desirably about 80° C. or less.

Another method of controlling the drying process, which may be usedalone or in combination with other controlled methods as disclosed aboveincludes controlling and modifying the humidity within the dryingapparatus where the film is being dried. In this manner, the prematuredrying of the top surface of the film is avoided.

Additionally, it has also been discovered that the length of drying timecan be properly controlled, i.e. balanced with the heat sensitivity andvolatility of the components, and particularly the flavor oils anddrugs. The amount of energy, temperature and length and speed of theconveyor can be balanced to accommodate such actives and to minimizeloss, degradation or ineffectiveness in the final film.

A specific example of an appropriate drying method is that disclosed byMagoon. Magoon is specifically directed toward a method of drying fruitpulp. However, the present inventors have adapted this process towardthe preparation of thin films.

The method and apparatus of Magoon are based on an interesting propertyof water. Although water transmits energy by conduction and convectionboth within and to its surroundings, water only radiates energy withinand to water. Therefore, the apparatus of Magoon includes a surface ontowhich the fruit pulp is placed that is transparent to infraredradiation. The underside of the surface is in contact with a temperaturecontrolled water bath. The water bath temperature is desirablycontrolled at a temperature slightly below the boiling temperature ofwater. When the wet fruit pulp is placed on the surface of theapparatus, this creates a “refractance window.” This means that infraredenergy is permitted to radiate through the surface only to the area onthe surface occupied by the fruit pulp, and only until the fruit pulp isdry. The apparatus of Magoon provides the films of the present inventionwith an efficient drying time reducing the instance of aggregation ofthe components of the film.

The films may initially have a thickness of about 500 μm to about 1,500μm, or about 20 mils to about 60 mils, and when dried have a thicknessfrom about 3 μm to about 250 μm, or about 0.1 mils to about 10 mils.Desirably, the dried films will have a thickness of about 2 mils toabout 8 mils, and more desirably, from about 3 mils to about 6 mils.

Uses of Thin Films

The thin films of the present invention are well suited for many uses.The high degree of uniformity of the components of the film makes themparticularly well suited for incorporating pharmaceuticals. Furthermore,the polymers used in construction of the films may be chosen to allowfor a range of disintegration times for the films. A variation orextension in the time over which a film will disintegrate may achievecontrol over the rate that the active is released, which may allow for asustained release delivery system. In addition, the films may be usedfor the administration of an active to any of several body surfaces,especially those including mucous membranes, such as oral, anal,vaginal, ophthalmological, the surface of a wound, either on a skinsurface or within a body such as during surgery, and similar surfaces.

The films may be used to orally administer an active. This isaccomplished by preparing the films as described above and introducingthem to the oral cavity of a mammal. This film may be prepared andadhered to a second or support layer from which it is removed prior touse, i.e. introduction to the oral cavity. An adhesive may be used toattach the film to the support or backing material which may be any ofthose known in the art, and is preferably not water soluble. If anadhesive is used, it will desirably be a food grade adhesive that isingestible and does not alter the properties of the active. Mucoadhesivecompositions are particularly useful. The film compositions in manycases serve as mucoadhesives themselves.

The films may be applied under or to the tongue of the mammal. When thisis desired, a specific film shape, corresponding to the shape of thetongue may be preferred. Therefore the film may be cut to a shape wherethe side of the film corresponding to the back of the tongue will belonger than the side corresponding to the front of the tongue.Specifically, the desired shape may be that of a triangle or trapezoid.Desirably, the film will adhere to the oral cavity preventing it frombeing ejected from the oral cavity and permitting more of the active tobe introduced to the oral cavity as the film dissolves.

Another use for the films of the present invention takes advantage ofthe films' tendency to dissolve quickly when introduce to a liquid. Anactive may be introduced to a liquid by preparing a film in accordancewith the present invention, introducing it to a liquid, and allowing itto dissolve. This may be used either to prepare a liquid dosage form ofan active, or to flavor a beverage.

The films of the present invention are desirably packaged in sealed, airand moisture resistant packages to protect the active from exposureoxidation, hydrolysis, volatilization and interaction with theenvironment. Referring to FIG. 1, a packaged pharmaceutical dosage unit10, includes each film 12 individually wrapped in a pouch or betweenfoil and/or plastic laminate sheets 14. As depicted in FIG. 2, thepouches 10, 10′ can be linked together with tearable or perforatedjoints 16. The pouches 10, 10′ may be packaged in a roll as depicted inFIG. 5 or stacked as shown in FIG. 3 and sold in a dispenser 18 as shownin FIG. 4. The dispenser may contain a full supply of the medicationtypically prescribed for the intended therapy, but due to the thinnessof the film and package, is smaller and more convenient than traditionalbottles used for tablets, capsules and liquids. Moreover, the films ofthe present invention dissolve instantly upon contact with saliva ormucosal membrane areas, eliminating the need to wash the dose down withwater.

Desirably, a series of such unit doses are packaged together inaccordance with the prescribed regimen or treatment, e.g., a 10-90 daysupply, depending on the particular therapy. The individual films can bepackaged on a backing and peeled off for use.

The features and advantages of the present invention are more fullyshown by the following examples which are provided for purposes ofillustration, and are not to be construed as limiting the invention inany way.

EXAMPLES Examples A-I

Water soluble thin film compositions of the present invention areprepared using the amounts described in Table 1.

TABLE 1 Weight (g) Ingredient A B C D E F G H I Hydroxypropylmethyl 1.761.63 32.00 3.67 32.00 cellulose Peppermint oil 0.90 1.0 1.05 8.0 2.67Sweetener 0.15 0.15 0.22 0.10 4.6 1.53 0.15 Polyvinylpyrrolidone 0.941.05 7.0 2.33 Tween 80¹ 0.5 0.5 2.0 0.65 11.80 1.35 0.5 11.80Simethicone² 0.2 0.2 0.15 0.30 1.80 0.21 0.2 1.80 Listerine³ 83.35 83.35Methylcellulose 6.0 Cornstarch⁴ 1.75 Agar 1.25 Water 42.24 93.63 39.22768.0 280.0 88.24 768.0 Loratadine⁵ 19.2 19.2 Pullulan⁶ 6.0 Ibuprofen38.4 ¹Available from ICI Americas ²Available from OSI ³Available fromPfizer, Inc. including thymol (0.064%), eucalyptol (0.092%), methylsalicylate (0.060%), menthol (0.042%), water (up to 72.8%), alcohol(26.9%), benzoic acid, poloxamer 407, sodium benzoate, and caramel color⁴Available from Grain Processing Corporation as Pure Cote B792⁵Available from Schering Corporation as Claritin ⁶Available fromHayashibara Biochemical Laboratories, Inc., Japan

The ingredients of inventive compositions A-I were combined by mixinguntil a uniform mixture was achieved. The compositions were then formedinto a film by reverse roll coating. These films were then dried on thetop side of an infrared transparent surface, the bottom side of whichwas in contact with a heated water bath at approximately 99° C. Noexternal thermal air currents were present above the film. The filmswere dried to less than about 6% by weight water in about 4 to 6minutes. The films were flexible, self-supporting and provided a uniformdistribution of the components within the film.

The uniform distribution of the components within the film was apparentby examination by either the naked eye or under slight magnification. Byviewing the films it was apparent that they were substantially free ofaggregation, i.e. the carrier and the actives remained substantially inplace and did not move substantially from one portion of the film toanother. Therefore, there was substantially no disparity among theamount of active found in any portion of the film.

Uniformity was also measured by first cutting the film into individualdosage forms. Twenty-five dosage forms of substantially identical sizewere cut from the film of inventive composition (E) above from randomlocations throughout the film. Then eight of these dosage forms wererandomly selected and additively weighed. The additive weights of eightrandomly selected dosage forms, are as shown in Table 2 below:

TABLE 2 Additive Weight (g) Sample Trial 1 Trial 2 1 0.04 0.04 2 0.080.08 3 0.12 0.12 4 0.16 0.16 5 0.20 0.20 6 0.24 0.24 7 0.28 0.28 8 0.320.32

The individual dosages were consistently 0.04 gm, which shows that thedistribution of the components within the film was consistent anduniform. This is based on the simple principal that each component has aunique density. Therefore, when the components of different densitiesare combined in a uniform manner in a film, as in the present invention,individual dosages forms from the same film of substantially equaldimensions, will contain the same mass.

An alternative method of determining the uniformity of the active is tocut the film into individual doses. The individual doses may then bedissolved and tested for the amount of active in films of particularsize. This demonstrates that films of substantially similar size cutfrom different locations on the same film contain substantially the sameamount of active.

When the films formed from inventive compositions A-H are placed on thetongue, they rapidly dissolve, releasing the active ingredient.Similarly, when they are placed in water, the films rapidly dissolvewhich provides a flavored drink when the active is chosen to be aflavoring.

Examples J-L

Thin films that have a controlled degradation time and includecombinations of water soluble and water insoluble polymers and watersoluble films that allow controlled release of an active are preparedusing approximately the amounts described in Table 3.

TABLE 3 Weight (g) Ingredient J K L Hydroxypropylmethyl cellulose 1.01.0 Tween 80¹ 0.7 0.7 0.7 Water 5.0 Aquacoat ECD² 17.0 17.0 17.5Peppermint oil 1.0 0.4 1.1 ¹Available from ICI Americas ²A 30% by weightaqueous dispersion of ethyl cellulose available from FMC

The components of inventive compositions J-L were combined and formedinto films using the methods for preparing inventive compositions A-Iabove. These films were also flexible, self-supporting and provided auniform distribution of active which permits accuracy in dosing.

The uniformity of the films prepared from inventive compositions J-L mayalso be tested by either visual means measuring the weights ofindividual dosage films, or by dissolving the films and testing for theamount of active as described above.

Examples M-O

An alternative method of preparing films which provides an accuratedosing may be used for any of inventive compositions A-I. The methodbegins with first combining the ingredients with mixing. The combinationof ingredients is then divided among individual wells or molds. In sucha method, aggregation of the components during drying is prevented bythe individual wells.

TABLE 4 Weight % Ingredient M N O 5% Methylcellulose Solution¹ 73.2244.22 74.22 Raspberry Flavor 3.28 3.28 3.28 Sweetener Blends 1.07 1.071.07 Tween-80² 2.47 2.47 2.47 Polyvinylpyrrolidone 3.30 3.30 3.30Ethanol 95% 8.24 8.24 8.24 Propylene Glycol 1.65 1.65 1.65 CalciumCarbonate 4.12 4.12 4.12 Cornstarch³ 1.65 1.65 1.65 Red Dye⁴ 1.00 CornSyrup⁵ 30.00 ¹Available from Dow Chemical Co. as Methocel K35 ²Availablefrom ICI Americas ³Available from Grain Processing Corporation as PureCote B792 ⁴Available from McCormick ⁵Available from Bestfoods, Inc. asKaro Syrup

The ingredients in the above Table 4 were combined and formed into afilm by casting the combination of ingredients onto the glass surfaceand applying heat to the bottom side of the glass. This providedinventive compositions M-O.

The film of composition M was examined both prior to and after dryingfor variations in the shading provided by the red dye. The film wasexamined both under sunlight and by incandescent bulb light. Novariations in shade or intensity of color were observed.

Further testing of the films of composition M included testing ofabsorption which is directly related to concentration. The film was cutinto segments each measuring 1.0 in. by 0.75 in., which wereconsecutively assigned numbers. Approximately 40 mg of the scrapmaterial from which the segments were cut was dissolved in about 10 mlof distilled water and then quantitatively transferred to a 25 mlvolumetric flask and brought to volume. The solution was centrifuged andscanned at 3 nm intervals from 203-1200 nm. The frequency of maximumabsorption was found to be 530 nm. The solution was then re-centrifugedat a higher RPM (for the same length of time) and re-scanned, whichdemonstrated no change in the % transmission or frequency.

Each of the segments were weighed to 0.1 mg and then dissolved in 10 mldistilled water and transferred quantitatively to a 25 ml volumetricflask and brought to volume with distilled water. Each segment solutionwas then centrifuged as above, and then scanned, at first from 203-1200nm and later from only 500 nm to 550 nm at a 1 nm scanning speed. Thevalue recorded was the % transmission at the lowest wave length, whichwas most frequently 530 nm.

The absorption values are shown in Table 5 below:

TABLE 5 Segment mg/% A 1-2 1.717 3-4 1.700 5-6 1.774 7* 1.701  9-101.721 11-12 1.729 13-14 1.725 15-16 1.713 *segment 8 was lost

The overall average absorption was 1.724. Of the 15 segments tested, thedifference between the highest and lowest values was 0.073 units, or 4%based on the average. This shows excellent control over the uniformityof the dye within the composition because the absorption is directlyproportional to the concentration of the dye within each segment.

The film of inventive composition N provided a very flexible film. Thisfilm was able to be stretched and exhibited a very high tensilestrength.

After forming the film of inventive composition O, the film was removedfrom the glass by very rapidly stripping the length of the glass with arazor. This provided very tightly wound “toothpick-like” dosage forms.Each dosage form consistently weighed 0.02 g. This demonstrates theuniformity of the dosage forms as well as the superior self-supportingproperties of the films.

Examples P-W

Compositions P—W were prepared to demonstrate the interaction amongvarious conditions in production of films as they relate to the presentinvention. The ingredients in the below Table 6 were combined and formedinto a film using the process parameters listed in Table 7 below,prepared in a 6 m drying tunnel designed to incorporate bottom drying ofthe films. Each of the examples shows the effect of different ingredientformulations and processing techniques on the resultant film products.

TABLE 6 Weight (g) Ingredient P Q R S T U V W Hydroxypropylmethyl 320320 320 320 320 320 345 345 cellulose Water 1440 1440 1440 1440 1440 999999 Sweetener 60 60 45 Mint Flavor 80 80 Propylene Glycol 50 50 50 100100 100 100 69.3 Xanthan 22 11 11.23 10 10 10 6.9 Water/Ethanol(60/40)1440 Orange Flavor 42

TABLE 7 Film Top¹ Bot.¹ Top² Thickness v v T¹ v (Micron) (m/sec) (m/sec)(° C.) (m/sec) P1 100 0 22 75 0 P2 350 0 22 75 0 P3 350 0 40 75 0 P4 3500 40 75 0 P5 350 10 40 75 10 Q 350 0 40 75 10 R 350 0 40 85 10 S1 250 040 100 0 S2 300 0 40 100 0 S3 350 0 40 100 0 T1 250 0 40 100 0 T2 350 040 100 0 U1 300 0 40 100 0 U2 250 0 40 100 0 U3 300 0 40 100 0 V1 300 040 100 0 V2 300 0 40 100 0 V3 300 0 40 100 0 W1 300 0 40 93 0 W2 250 040 90 0 W3 200 0 40 90 0 Bot.² Film Coater v T² Weight Speed % (m/sec)(° C.) (g) m/min Moisture P1 23 60 109 5 >20 P2 23 60 n/a 5 >20 P3 40 60161 3 >20 P4 40 75 191 3 >20 P5 40 75 253 3 >20 Q 40 75 n/a 3 >20 R 0 852.5 >20 S1 40 90 163 1.5 <5 S2 40 90 193 1.5 <5 S3 40 90 225 1.5 <5 T140 90  64 1.5 <5 T2 40 90  83 1.5 <5 U1 40 90 208 1.5 20 U2 40 90 1771.5 20 U3 40 90 212 1.3 20 V1 40 90 237 1.3 20 V2 40 100 242 1.3 20 V340 100 221 1 6 W1 40 90 220 1.3 5 W2 40 90 199 1.3 5 W3 40 90 169 1.3 5¹First Heater Section (3 m) ²Second Heater Section (3 m)

In Table 7, each of the process parameters contributes to differentproperties of the films. Film thickness refers to the distance betweenthe blade and the roller in the reverse roll coating apparatus. Bottomvelocity and top velocity refer to the speed of air current on thebottom and top sides of the film, respectively. The film weight is ameasure of the weight of a circular section of the substrate and thefilm of 100 cm².

Compositions P-R show the effects of visco-elastic properties on theability to coat the film composition mixture onto the substrate for filmformation. Composition P displayed a stringy elastic property. The wetfilm would not stay level, the coating was uneven, and the film did notdry. In Composition Q, substantially the same formulation as P was usedhowever the xanthan was not included. This product coated the substratebut would not stay level due to the change in the visco-elasticproperties of the wet foam. Composition R was prepared usingsubstantially the same formulation, but incorporated one-half of theamount of xanthan of Composition P. This formulation provided acomposition that could be evenly coated. Compositions P-Q demonstratethe importance of proper formulation on the ability of the film matrixto conform to a particular coating technique.

The films produced from Composition S contained a large amount of air inthe films. This is shown by the dried film thickness which was the samedespite that variation in the coated thickness as in Table 7.Microscopic examination of the film revealed a large number of airbubbles in the film. In order to correct for the addition of air in thefilms, care must be taken in the mixing process to avoid air inclusion.

Composition T included a change in the solvent to 60/40 water ethanol.Composition T was stirred slowly for 45 min. to deaerate the mixture.The dried weight film products T1 and T2 were consistent with theincrease in solids from T1 to T2. The films dried much faster with lessthan 5% moisture. With the particular combination of ingredients inComposition T, the substitution of part ethanol for part water allowedthe film to dry more quickly. The elimination of air from the film as aresult of the slow stirring also contributed to the uniformity of thefinal film product and the faster drying time.

Only water was used as a solvent in Composition U. The dried weight ofthe U1-U3 changed consistently in accordance with the change in coatingthickness indicating that no air bubbles were present. However, thesefilms contained 20% moisture upon exit from the oven, unlike the filmsof Composition T, which included part ethanol and dried completely.

The amount of solids was increased and the amount of water was decreasedin Compositions V1 and V2. The dried weight was greater than U1-U3 dueto the increase in solids, however the films still contained 20%moisture upon exit from the oven, similar to Composition U.

The coating line speed was reduced for Composition V3, to preventpremature drying of the exposed top film surface. This film productdried to 6% moisture.

While increasing the amount of solids improved the film weight, longerdrying times were required. This was due to the surface of the filmsealing preventing easy removal of the water. Therefore, forCompositions W1-W3, the temperature in the first 3 m section of thedryer was decreased. This prevented the premature drying of the topsurface of the films. Even at greater film thicknesses, the films weredried to 5% moisture even at faster coater line speeds.

Examples X-AA

TABLE 8 Weight (g) Ingredient X Y Z AA Loratadine 104.69 Zomig 52.35Paxil 104.69 Hydroxypropyl methylcellulose 320 320 320 150 Sweetenerblend 60 60 60 0.4 Simethicone 1.5 1.5 1.5 1.5 Propylene glycol 100 100100 Water 1440 1440 1440 790 Cream essence 0.4 Polyvinyl pyrrolidinone 4Ethanol 40 Cocoa 55.2 Polyoxyl-40-stearate 7

Compositions X, Y and Z of Table 8 were taste mask coated using a Glattcoater and Eudragit E-100 polymethacrylate polymer as the coating. Thecoating was spray coated at a 20% level. Therefore 10 mg of drug 12.5 mgof the final dry product must be weighed.

The base formula which excluded the drug additive was mixed with care tonot incorporate air. After initial mixing the formula was slowly mixedto deaerate over 30 min. During this time the drug was weighed andprepared for addition to the base mix.

For Composition X, the Loratadine (80% drug) was added slowly to the mixwith stirring. After 5 min. of stirring, the total mix was added to thepan of a three roll coater set (reverse roll coater) at 30 microncoating thickness.

The process bottom temperature was set at 90° C. with no top heat orair, the bottom air velocity was set at 40 m/sec., and the line speedwas set at 1.3 m/min. Total drying time for the film was 4.6 min.

The liquid was coated at 30 microns and dried in the oven in less than 5min. The film was flexible and a ″×0.75″ piece weighed 70 mg andcontained 10 mg of Loratadine.

The experiment was repeated for Compositions Y and Z, Zomig and Paxil,respectively. Both produced flexible films with the target weight of 70mg containing 5 mg of Zomig and 70 mg containing 10 mg of Paxil,respectively.

The products were sweet without any noticeable drug aftertaste.

The ingredients of Composition AA were mixed in order to reduce aircaptured in the fluid matrix. After mixing 45 g of loratadine coated ata 80% active level and 20% coating using Eudragit E-100, this mixturewas added slowing with mixing until the drug was evenly dispersed,approximately 5 min. The liquid was then deposited into the 3 rollcoater (reverse roll coater) and coated at 30 microns at a line speed of1.3 m/min. The oven temperature was set at 90° C. to apply air and heatto the bottom only, with an air velocity set at 40 msec. The dried filmwas 0.005 inch. thick (5 mil) and was cut into 1 in.×0.75 in. piecesweighing 70 mg+/−0.7 mg, demonstrating the uniformity of the compositionof the film. The film was flexible with 5% moisture, free of airbubbles, and had uniform drug distribution as seen under the lightmicroscope, as well as shown by the substantially identical weightmeasurements of the film pieces.

Examples BA-BI

The incorporation of the anti-foaming/de-foaming agent (i.e.,simethicone) provided a film that not only provided a uniform film thatsubstantially reduced or eliminated air bubbles in the film product, butalso provided other benefits. The films displayed more desirableorganoleptic properties. The films had an improved texture that was less“paper-like” provided a better mouth-feel to the consumer.

The compositions in Table 9 were prepared (including the addition ofsimethicone in inventive compositions BA-BG) and mixed under vacuum toremove air bubbles.

The resultant uncut films of inventive compositions BA-BG exhibiteduniformity in content particularly with respect to the insoluble active,as well as unit doses of ¾″ by 1″ by 5 mils cut therefrom. The inventivecompositions also were observed to have a smooth surface, absent of airbubbles. The significantly higher amounts of simethicone present ininventive compositions BF-BG also provided a very uniform film, but notsignificantly improved from that of inventive compositions BA-BE.

By contrast, comparative examples BH-BI were observed to have a roughersurface, exhibiting the inclusion of air bubbles in the resultant filmwhich provided a less uniform texture and distribution of theingredients.

TABLE 9 Ingredient BA BB BC BD BE BF BG BH BI Hydroxypropylmethyl 0 3.773.70 3.84 0 3.67 0 0 3.84 cellulose Peppermint oil 2.94 1.93 2.39 0 02.67 2.94 2.67 0 Sweetener 2.20 0.32 0.23 0 0.17 1.53 2.20 1.54 0Polyvinylpyrrolidone 2.68 2.01 2.39 0 0 2.33 2.68 2.34 0 Tween 80¹ 2.241.07 1.48 1.42 0.55 1.35 2.24 0 1.42 Simethicone² 0.66 0.42 0.68 0.220.22 5.00 2.00 0 0 Listerine³ 0 0 0 0 92.41 0 0 0 0 Methylcellulose 4.030 0 0 0 0 4.03 0 0 Cornstarch⁴ 2.68 0 0 0 0 0 2.68 0 0 Water 73.53 90.4789.14 92.22 0 83.45 72.19 93.46 92.44 Loratadine⁵ 4.29 0 0 2.31 0 0 4.290 2.31 Pullulan⁶ 0 0 0 0 6.65 0 0 0 0 Calcium Carbonate 1.43 0 0 0 0 01.43 0 0 Xanthan Gum 0.30 0 0 0 0 0 0.30 0 0 Propylene Glycol 3.02 0 0 00 0 3.02 0 0 ¹Available from ICI Americas ²Available from OSI ³Availablefrom Pfizer, Inc. including thymol (0.064%), eucalyptol (0.092%), methylsalicylate (0.060%), menthol (0.042%), water (up to 72.8%), alcohol(26.9%), benzoic acid, poloxamer 407, sodium benzoate, and caramel color⁴Available from Grain Processing Corporation as Pure Cote B792⁵Available from Schering Corporation as Claritin ⁶Available fromHayashibara Biochemical Laboratories, Inc., Japan

Examples CA-CC

The following examples of the present invention describe films andfilm-forming compositions that use an ethoxylated caster oil as asurfactant, or alternatively are free of surfactants, plasticizersand/or polyalcohols. Desirably, the films or film-forming compositionsof the present invention are essentially free of surfactants. Moreover,the films or film-forming compositions of the present invention aredesirably formulated to be essentially free of surfactants. Furthermore,the films or film-forming compositions of the present invention aredesirably formulated to be essentially free of plasticizers. Stillfurthermore, the films or film-forming compositions of the presentinvention are desirably formulated to be essentially free ofpolyalcohols. Moreover, the films or film-forming compositions of thepresent invention are desirably formulated to be essentially free ofsurfactants and plasticizers. Furthermore, the films or film-formingcompositions of the present invention are desirably formulated to beessentially free of surfactants, plasticizers and polyalcohols.

TABLE 10 (parts by wt.) Ingredient CA POLYMERS: Hydroxypropylmethylcellulose 15.6 Cornstarch¹ 10.41 Polyvinylpyrrolidone 10.41 Xanthan Gum1.14 SURFACTANT²: 2.0 PLASTICIZER³: 11.67 ANTI-FOAM AGENT⁴ 2.44 OTHERSpearmint Flavor 10.43 Loratadine (drug) 16.62 Calcium Carbonate 5.54Sweetener 9.36 ¹Available from Grain Processing Corporation as Pure CoteB792 ²Ethoxylated caster oil, Cremophor ® EL available from BASF³Propylene Glycol ⁴Silicone Emulsion

The above ingredients were added at 30% to 70% water and stirred untilpolymers were fully hydrated which took 45 min. The mix was then putunder vacuum to eliminate entrapped air. Vacuum was added in a steadymanner starting at 500 mm and progressing up to 760 mm over 45 min.

After release of the vacuum, 6 grams of the liquid was added to acoating paper using a 200 micron spiral wound rod and a K Control CoaterModel 101 (RK Print Coat Inst. Ltd.). The paper substrate onto which thecoating was added was a silicone coated paper. The coated paper was thendried at 90° C. until about 5% moisture remained. The formula coated anddried to a film thickness of approx. 60 microns and quickly dissolved inthe mouth.

TABLE 11 (parts by wt.) Ingredient CB POLYMERS: Hydroxypropylmethylcellulose 15.6 Cornstarch¹ 10.41 Polyvinylpyrrolidone 10.41PLASTICIZER/SOLVENT²: 22.1 ANTI-FOAM AGENT³ 2.44 OTHER Raspberry Flavor0.3 Calcium Carbonate⁴ 30.38 Sweetener 8.36 ¹Available from GrainProcessing Corporation as Pure Cote B792 ²Propylene Glycol ³PolydimethylSiloxane Emulsion ⁴Functioned to mimic drug loading

The above ingredients were added to water at 40% until a homogeneoussuspension was made. Vacuum was added over 20 min. starting at 500 mmHg. and ending at 660 mm Hg. until all air was removed from suspension.Film was made as described in prior experiments. The liquid coated thesilicone release substrate and dried to a uniform flexible film. Thefilm passed the 180° bend test without cracking and dissolved in themouth.

TABLE 12 (parts by wt.) Ingredient CC POLYMERS: Hydroxypropylmethylcellulose 7.8 Hydroxypropyl cellulose 7.8 ANTI-FOAM AGENT¹ 0.75 OTHERPeppermint & Bittermint Flavor 2.25 Tastemasking Flavor² 0.3 CalciumCarbonate³ 15.2 Sweeteners 0.9 ¹Polydimethyl Siloxane Emulsion ²Prosweetfrom Virginia Dave ³Functioned to mimic drug loading

The above ingredients were added at 30% to 70% water and stirred untilpolymers were fully hydrated which took 20 min. The mix was then putunder vacuum to eliminate entrapped air. Vacuum was added in a steadymanner up to 760 mm over 35 min.

After release of the vacuum, the liquid was added to a coating paperusing a 350 micron smooth bar and a K Control Coater Model 101 (RK PrintCoat Inst. Ltd.). The paper substrate onto which the coating was addedwas a silicone coated paper. The coated paper was then dried at 90° C.until about 4% moisture remained. The formula coated and dried to afilm. The film had an acceptable taste and quickly dissolved in themouth. The taste-masking flavor is an ingredient that affects the tastereceptors to mask the receptors from registering a different, typicalundesirable, taste. The film passed the 180° bend test without crackingand dissolved in the mouth.

Example CD

The following example of the present invention describe films andfilm-forming compositions that use a taste-masked, pharmaceuticallyactive agent which also contains flavors and taste-masking aids. Ataste-masking flavor is an ingredients that effects taste receptors tomask the receptors from registering a different, typically undesirable,taste.

TABLE 13 (grams) Ingredient CD Hydroxypropylmethyl cellulose 4.26Hydroxypropyl cellulose 1.42 Precipitated calcium Carbonate 1.22Sweetner¹ 0.6 Taste-Masking flavor² 0.08 Taste-masked Acetaminophen³5.86 Cinnamon Flavor 0.9 Spearmint Flavor 0.43 Polydimethylsiloxaneemulsion 0.23 ¹Sucralose, available from McNeil Nutritionals ²MagnaSweet, available from Mafco Worldwide Corp. ³Gutte Enteric, coatedacetaminophen, Gatte, LLC

The above ingredients, except for the pharmaceutically active agent andflavors, were added at 35 grams water and stirred until polymers werefully hydrated which took about 20 min. Food coloring (7 drops of redfood coloring and 1 drop of yellow fool coloring) was also added. Themix was then put under vacuum to eliminate entrapped air. Vacuum wasadded in a steady manner starting at 500 mm and progressing up to 760 mmover about 10 to 20 minutes. The taste-masked Acetaminophen was added tothe mix in about 4 minutes was stirring under vacuum. The flavors werethen added to the mix in about 4 minutes was stirring under vacuum.

After release of the vacuum, the liquid solution was added to a coatingpaper using a 350 micron smooth bar. The paper substrate onto which thecoating was added was a silicone coated paper. The coated paper was thendried at 90° C. for about 11 minutes until about 3% moisture remained.

The formula coated and dried to a film. The film had an acceptable tasteand moderately quickly dissolved in the mouth. The film did not curl onstanding. The film passed the 180° bend test without cracking anddissolved in the mouth.

While there have been described what are presently believed to be thepreferred embodiments of the invention, those skilled in the art willrealize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention, and it is intended toinclude all such changes and modifications as fall within the true scopeof the invention.

Examples CE-CF

Thin film compositions of the present invention were prepared using theamounts described in Table 14.

TABLE 14 Ingredient Weight (g) Hydroxypropylmethyl cellulose 3.92Pullulan 3.92 Trehalose¹ 3.5 Precipitated Calcium Carbonate 3.85Propylene Glycol 1.96 Simethicone² 0.35 Bovine Extract³ 32.5 Water q.s.¹Available from Cargill Inc. ²Available from Sentry ³Available fromAmarillo Biosciences Inc.

The above ingredients were combined by mixing until a uniform mixturewas achieved. A sufficient amount of water was present in the filmcompositions prior to drying, i.e., q.s., which may range between about200 g to about 1000 g. The compositions then were cast into films ontorelease paper using a K-Control Coater with a 250 micron smooth bar.

In Example CE, the films subsequently were dried in an oven atapproximately 80° C. for about 6 minutes. The films were dried to about4.3 percent moisture. In Example CF, the films were dried in an oven atapproximately 60° C. for about 10 minutes. The films were dried to about5.06 percent moisture. After drying, the protein derived from bovineextract, which was contained in the films, was tested to determinewhether or not it remained active. The protein was found to beapproximately 100 percent active in the final, dried film products ofboth Examples CE and CF. Therefore, the heat sensitive active did notsubstantially degrade or denaturize during the drying process.

Examples CG-CI Example CG

Thin film compositions of the present invention were prepared using theamounts described in Table 15.

TABLE 15 Weight (g) Ingredient CG CH Hydroxypropylmethyl cellulose 4.599.18 Hydroxypropyl cellulose 1.53 3.06 Sucralose¹ 0.7 1.4 Magna Sweet²0.09 0.18 Precipitated calcium carbonate 2.0 4 Fat-coateddextromethorphan 5.96 11.93 hydrobromide Orange concentrate 1.05 2.1Prosweet MM24³ 0.18 0.35 Propylene glycol 1.22 2.45 Simethicone⁴ 0.180.35 Water 32.5 65 ¹Available from McNeil Nutritional ²Available fromMafco Worldwide Corp. ³Available from Virginia Dare ⁴Available fromSentry

The above ingredients were combined by mixing, and then cast into twofilms on release paper using a K-Control Coater with a 350 micron smoothbar. The films were subsequently dried according to conventional dryingtechniques, rather than via the uniform drying process of the presentinvention. One film was dried in an oven at 80° C. for 9 minutes on awire rack. The second film was dried in an oven at 80° C. for 9 minuteson a wire screen. Both films were dried to about 2.4 percent moisture.

The resulting dried films showed imprints of the wire rack and screenafter drying. In particular, the films exhibited aggregations ofparticles in both line and diamond configurations, as shown in FIGS.9-16. These configurations comprise imprints of wire supports typicallyused in the drying process. Without uniform heat diffusion, the wiresupports conducted heat more intensely at the points of contact with thesubstrate, leading to increased evaporation at these points. This causedmore vigorous mixing, thereby pulling more particles to the contactpoints. The resulting increased particle density at the contact pointsis depicted in FIGS. 9-16.

Example CH

A composition including the ingredients of Example CH was combined andformed into films, as in Example CG. The films were dried by the processof the present invention, under the same time and temperature conditionsas in Example CG. In particular, the films were dried in an 80° C. airoven for 9 minutes on trays lined with furnace filters. The films weredried to about 1.89 percent moisture. The resulting films had nostreaks, and were homogenous. Due to uniform heat diffusion throughoutthe film, no particle aggregations developed, as depicted in FIG. 17.

1. An ingestible film product containing a desired level of apharmaceutical or biological active component formed by the steps of:(a) combining a water-soluble polymer, water and a pharmaceutical orbiological active component to form a material having a substantiallyuniform distribution of components; (b) forming said material into afilm; (f) providing a conveyor surface having top and bottom sides; (g)feeding said film onto said top side of said surface; and (h) dryingsaid film within about 10 minutes or fewer by applying heat to saidbottom side of said conveyor surface with substantially no hot aircurrents on the top side of said surface at a temperature above adegradation temperature of said pharmaceutical or biological activecomponent, wherein said degradation temperature is 70° C. or higher,wherein said pharmaceutical or biological active component is maintainedat said desired level, and wherein said water is present in said driedfilm at about 10% by weight of said film or less.
 2. The film product ofclaim 1, wherein said water added in step (a) has a weight percent of atleast about 30%.
 3. The film product of claim 1, wherein said drying ofsaid film reduces the weight percent of said water to about 8% or less.4. The film product of claim 1, wherein said drying of said film reducesthe weight percent of said water to about 6% or less.
 5. The filmproduct of claim 1, wherein said polymer is a cellulose derivative. 6.The film product of claim 1, wherein said polymer is a member selectedfrom the group consisting of hydroxypropylmethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium aginate, polyethylene glycol,xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum,polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers,starch and combinations thereof.
 7. The film product of claim 1, whereinsaid film product has a thickness of greater than about 0.1 mils.
 8. Thefilm product of claim 1, wherein said film product has a thickness ofabout 10 mils or fewer.
 9. The film product of claim 1, wherein saidfilm product has a substantially uniform thickness.
 10. The film productof claim 1, wherein said film product is divided into dosage forms ofsubstantially equal dimensions.
 11. The film product of claim 10,wherein said dosage forms contain an amount of said pharmaceutical orbiological active that varies about 10% or less among said dosage forms.12. The film product of claim 1, wherein said pharmaceutical orbiological active component is a protein.
 13. The film product of claim1, wherein said pharmaceutical or biological active component istaste-mask coated.
 14. An ingestible film product containing a desiredlevel of a pharmaceutical or biological active component formed by thesteps of: (a) forming a master-batch premix of a water-soluble polymerand water; (b) feeding a predetermined amount of said premix to at leastone mixer; (c) adding a pharmaceutical or biological active component tosaid at least one mixer; (d) mixing said pharmaceutical or biologicalactive component and said predetermined amount of said premix to form amaterial having a substantially uniform distribution of components; (e)forming said material into a film; (f) providing a conveyor surfacehaving top and bottom sides; (g) feeding said film onto said top side ofsaid surface; and (h) drying said film by applying heat to said bottomside of said conveyor surface at a temperature above a degradationtemperature of said pharmaceutical or biological active component,wherein said degradation temperature is 70° C. or higher, wherein saiddrying step further comprises rapidly forming a visco-elastic filmwithin about the first 4.0 minutes by applying heat to said bottom sideof said surface in the absence of hot air currents on the top side ofsaid surface; and drying said visco-elastic film to form aself-supporting ingestible film, wherein said pharmaceutical orbiological active component is maintained at said desired level, andwherein said water is present in said dried film at about 10% by weightof said film or less.
 15. The film product of claim 14, wherein saidfilm product is divided into dosage forms of substantially equaldimensions.
 16. The film product of claim 15, wherein said dosage formscontain an amount of said pharmaceutical or biological active thatvaries about 10% or less among said dosage forms.
 17. The film productof claim 14, wherein said pharmaceutical or biological active componentis a protein.
 18. The film product of claim 14, wherein saidpharmaceutical or biological active component is taste-mask coated.